Derivatives of 1-(oxoaminoacetyl) pentylcarbamate as cathepsin k inhibitors for the treatment of bone loss

ABSTRACT

Heterocycle substituted ketoamide derivatives of Formula (I), wherein the substitutes A, D, A and R are defined as in claim in, which are useful as cathepsin K inhibitors are described herein. The described invention also includes methods of making such heterocycle substituted ketoamide derivatives as well as method of using the same in the manufacture of medicaments for the treatment of disorders, including osteoporosis, associated with an imbalance between bone resorption and formation which can ultimately lead to fracture.

FIELD OF THE INVENTION

The present invention relates to heterocycle substituted ketoamidederivatives, compositions and medicaments containing the same, as wellas processes for the preparation and use of such compounds, compositionsand medicaments. Such ketoamide derivatives are inhibitors of serine andcysteine proteases. In particular, such ketoamide derivatives areinhibitors of cysteine proteases of the papain superfamily. Moreparticularly, the ketoamides of the present invention are inhibitors ofcathepsin family cysteine proteases such as cathepsin K. Further, suchketoamide derivatives are useful in the treatment of diseases associatedwith serine and cysteine protease activity, more particularly, in thetreatment of diseases associated with cathepsin family cysteineproteases, for instance in the treatment of diseases associated withcathepsin K activity.

BACKGROUND OF THE INVENTION

Osteoclasts are multinuclear cells of hematopoietic lineage, whichfunction in the process of bone resorption. Typically, osteoclastsadhere to a bone surface and form a tight sealing zone. This activity isfollowed by extensive membrane ruffling on the surface of theosteoclasts. Such action creates an enclosed extracellular compartmenton the bone surface that is acidified by proton pumps in the ruffledmembrane and into which the osteoclast secretes proteolytic enzymes. Thelow pH of the compartment dissolves hydroxyapatite crystals at the bonesurface, while the proteolytic enzymes digest the protein matrix. Inthis way a resorption pit is formed, after which the osteoclast releasesfrom the surface of the bone. At the completion of this cycle,osteoblasts remodel the bone; that is, the osteoblasts deposit a newprotein matrix, which is subsequently mineralized, at this zone.

Normally, a balance exists between the processes of bone resorption andnew bone formation during remodeling. This normal balance of boneresorption and bone formation may be disrupted, resulting in a net lossof bone in each cycle of remodeling. Such net bone loss may lead toosteoporosis. Osteoporosis is characterized by reduced bone mass anddisruptions in the microarchitecture of the bone. These characteristicsmay lead to fractures, which can result from a minimal amount of trauma.Typical sites of fractures include vertebral bodies, distal radius, andthe proximal femur. However, because those suffering from osteoporosishave general skeletal weakness, fractures may occur at other sites.

Since osteoporosis is characterized by an increase in bone resorptionwith respect to bone formation, therapeutic agents that suppress boneresorption would be expected to provide a suitable treatment forosteoporosis. Administration of estrogens or calcitonin has been thebone resorption suppression treatment typically employed. However, thesetreatments do not always achieve the desired effect. Consequently, thereis a continuing need for therapeutic agents that attenuate boneresorption in a subject in need of such attenuation.

Cathepsin K, which has also been called cathepsin O, cathepsin O2, andcathepsin X, is a member of the cysteine cathepsin family of enzymes,which are part of the papain superfamily of cysteine proteases. Otherdistinct cysteine protease cathepsins, designated cathepsin B, cathepsinC, cathepsin F, cathepsin H, cathepsin L, cathepsin O, cathepsin S.cathepsin V (also called L2), cathepsin W.

cathepsin Z (also called cathepsin X), have also been described in theliterature. Cathepsin K polypeptide and the cDNA encoding suchpolypeptide have been disclosed in U.S. Pat. No. 5,501,969. A crystalstructure for cathepsin K has also been disclosed in PCT PatentApplication WO 97/16177, published May 9, 1997. It has been reportedthat cathepsin K is abundantly expressed in osteoclasts under normalconditions and may be the major cysteine protease present in thesecells. (See Tezuka, et al., J. Biol. Chem., 1994, 269, 1106; Inaoka, etal, Biochem. Biophys. Res. Commun., 1995, 206, 89; and Shi, et al., FEBSLett., 1995, 357,129.) This abundant selective expression of cathepsin Kin osteoclasts suggests that this enzyme is essential for boneresorption. Thus, selective inhibition of cathepsin K may provide aneffective treatment for diseases of excessive bone loss, such asosteoporosis.

The selective inhibition of cathepsin K may also be useful in treatingother diseases. Such disorders include autoimmune diseases such asrheumatoid arthritis, osteoarthritis, neoplastic diseases, parasiticdiseases, and atherosclerosis. For instance, cathepsin K is expressed inthe synovium and synovial bone destruction sites of patients withrheumatoid arthritis (see Votta, B. J. et al.; J. Bone Miner. Res. 1997,12, 1396; Hummel, K. M. et al., J. Rheumatol. 1998, 25, 1887; Nakagawa,T. Y. et al., Immunity 1999, 10, 207; Otsuka, T. et al., S. J. Antibiot.1999, 52, 542; L1, Z. et al, Biochemistry 2000, 39, 529; Diaz, A. et al,Mol. Med. 2000, 6, 648; Moran, M. T. et al., Blood 2000, 96, 1969).Cathepsin K levels are elevated in chondroclasts of osteoarthriticsynovium (See Dodds, R. A. et al., Arthritis Rheum. 1999, 42, 1588;Lang, A. et al., J. Rheumatol. 2000, 27, 1970). Neoplastic cells alsohave been shown to express cathepsin K (see Littlewood-Evans, A. J. etal, J. A. Cancer Res. 1997, 57, 5386; Komarova, E. A., et al., Oncogene1998, 17, 1089; Santamaria, I., et al., Cancer Res. 1998, 58, 1624;Blagosklonny, M. V. et al., Oncogene 1999, 18, 6460; Kirschke, H. etal., Eur. J. Cancer 2000, 36, 787; Zhu, D.-M. et al., Clin. Cancer Res.2000, 6, 2064). Cysteine protease inhibitors have been suggested aschemotherapy for parasitic diseases (see McKerrow, J. H. Int. J.Parasitol. 1999, 29, 833; Selzer, P. M. et al., Proc. Natl. Acad. Sci.U.S.A. 1999, 96, 11015; Caffrey, C. R. et al, Curr. Drug Targets 2000,1,155; Du, X. et al., Chem. Biol. 2000, 7,733; Hanspal, M. Biochim.Biophys. Acta 2000, 1493, 242; Werbovetz, K. A. Curr. Med. Chem. 2000,7, 835). Elastolytic cathepsins S and K are shown to be expressed inhuman atheroma (see Sukhova, G. K. et al., J. Clin. Invest. 1998, 102,576-583; Parks, W. C. J. Clin. Invest 1999, 104, 1167; Shi, G.-P. etal., J. Clin. Invest. 1999, 104, 1191; Cao, H. et al., J. Hum. Genet2000, 45, 94).

The present inventors have now discovered novel heterocycle substitutedketoamide derivative compounds that are inhibitors of serine andcysteine protease activities, more particularly, cathepsin familycysteine protease activities, and most particularly, cathepsin Kactivity. Such ketoamide derivatives are useful in the treatment ofdisorders associated with serine and cysteine protease activity,including osteoporosis, Paget's disease, hypercalcemia of malignancy,metabolic bone disease, osteoarthritis, rheumatoid arthritis,periodontitis, gingivitis, atherosclerosis, and neoplastic diseasesassociated with cathepsin K activity.

BRIEF SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided a compoundof Formula (I):

or a salt, solvate, or physiologically functional derivative thereofwherein

-   A is the group defined by (Q⁴)_(p)-(Q³)_(n)-(Q²)_(m)-(Q¹)-, wherein    -   Q¹ is heterocyclyl or heterocyclylene,    -   Q² is OC(O), C(O), N(H)C(O), C(O)N(H)C(O), S(O)₂N(H)C(O), S(O)₂,        or N(H)S(O)₂, and m is 0 or 1,    -   Q³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, aralkyl,        aralkylene, aryl, arylene, heteroaryl, heteroarylene,        heterocyclyl, or heterocyclylene, and n is 0 or 1, and    -   Q⁴ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, aryl, aryloxy, heteroaryl,        halo, or cyano, and p is 0, 1, or 2;-   D is O or S;-   R is hydrogen or —N(R¹)—R²—R³;-   R¹ is hydrogen or C₁-C₆ alkyl;-   R² is C(O), C(O)O, C(O)N(H), S(O)₂, or S(O)₂N(H);-   R³ is hydrogen or C₁-C₆ alkyl;-   Z is the group defined by —(X)_(m)—(X¹), wherein    -   X is C(R′)(R″), wherein R′ is hydrogen or C₁-C₆ alkyl, R″ is        hydrogen or C₁-C₆ alkyl, and m is 0, 1, or 2; and    -   X¹ is aryl, heteroaryl, or heterocyclyl.

In a second aspect of the present invention, there is provided acompound of formula II:

or a salt, solvate, or physiologically functional derivative thereofwherein

-   A′ is the group defined by (Q⁴)_(p)-(Q³)_(n)-(Q²)_(m)-, wherein    -   Q² is OC(O), C(O), N(H)C(O), C(O)N(H)C(O), S(O)₂N(H)C(O), S(O)₂,        or N(H)S(O)₂, and m is 0 or 1,    -   Q³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, aralkyl,        aralkylene, aryl, arylene, heteroaryl, heteroarylene,        heterocyclyl, or heterocyclylene, and n is 0 or 1, and    -   Q⁴ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, aryl, aryloxy, heteroaryl,        halo, or cyano, and p is 0, 1, or 2;-   R^(a) is hydrogen or oxo;-   R^(b) is hydrogen or C₁-C₆ alkyl;-   R^(c) is hydrogen or C₁-C₆ alkyl;-   R is hydrogen or —N(R¹)—R²—R³;-   R¹ is hydrogen or C₁-C₆ alkyl;-   R² is C(O), C(O)O, C(O)N(H), S(O)₂, or S(O)₂N(H);-   R³ is hydrogen or C₁-C₆ alkyl;-   Z is the group defined by —(X)_(m)—(X¹), wherein    -   X is C(R′)(R″), wherein R′ is hydrogen or C₁-C₆ alkyl, R″ is        hydrogen or C₁-C₆ alkyl, and m is 0, 1, or 2; and

X¹ is aryl, heteroaryl, or heterocyclyl.

In a third aspect of the present invention, there is provided apharmaceutical composition, comprising: a therapeutically effectiveamount of a compound of formula (I), or a salt, solvate, or aphysiologically functional derivative thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.

In a fourth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being characterized bybone loss, comprising: administering to said mammal a therapeuticallyeffective amount of a compound of formula (I) or a salt, solvate or aphysiologically functional derivative thereof.

In a fifth aspect of the present invention, there is provided a compoundof formula (I), or a salt, solvate, or a physiologically functionalderivative thereof for use in therapy.

In a sixth aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof in the preparation of a medicament for usein the treatment of a disorder characterized by bone loss.

In a seventh aspect of the present invention, there is provided a methodof treating osteoporosis, comprising: administering to said mammal atherapeutically effective amount of a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof.

In an eighth aspect of the present invention, there is provided a methodof treating osteoporosis, comprising: administering to said mammaltherapeutically effective amounts of (i) a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof and (ii)at least one bone building agent such as parathyroid hormone (PTH).

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount that, as compared toa corresponding subject who has not received said amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkyl” asused herein include, but are not limited to, n-butyl, n-pentyl,isobutyl, isopropyl, and the like.

As used herein, the term “C₁-C₆ alkyl” refers to an alkyl group, asdefined above, which contains at least 1, and at most 6, carbon atoms.Examples of “C₁-C₆ alkyl” groups useful in the present inventioninclude, but are not limited to, methyl, ethyl, propyl, isopropyl,isobutyl, n-butyl, tert-butyl, and isopentyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

As used herein, the terms “C₁-C₃ alkylene” and “C₁-C₄ alkylene” refer toan alkylene group, as defined above, which contains at least 1, and atmost 3 or 4, carbon atoms respectively. Examples of “C₁-C₃ alkylene”groups useful in the present invention include, but are not limited to,methylene, ethylene, and n-propylene.

As used herein, the term “halogen” refers to fluorine, chlorine,bromine, or iodine and the term “halo” refers to fluoro (—F), chloro(—Cl), bromo (—Br), or iodo (—I).

As used herein, the term “haloalkyl” refers to an alkyl group, asdefined herein, substituted with at least one halo, halo being asdefined herein. Examples of branched or straight chained “haloalkyl”groups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substitutedindependently with one or more halo groups, e.g., fluoro, chloro, bromoand iodo.

As used herein, the term “C₁-C₆ haloalkyl” refers to haloalkyl asdefined above containing at least 1, and at most 6 carbon atomssubstituted with at least one halo group, halo being as defined herein.Examples of branched or straight chained “C₁-C₆ haloalkyl” groups usefulin the present invention include, but are not limited to methyl, ethyl,propyl, and isopropyl, substituted independently with one or morehalogens, e.g., fluoro, chloro, bromo, and iodo.

As used herein, the term “C₃-C₇ cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to seven carbon atoms, whichoptionally includes a C₁-C₄ alkylene linker through which it may beattached. Exemplary “C₃-C₇ cycloalkyl” groups include, but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

As used herein, the term “C₃-C₇ cycloalkylene” refers to a non-aromaticalicyclic divalent hydrocarbon radical having from three to seven carbonatoms, optionally substituted with substituents selected from the groupwhich includes C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, C₁-C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene rings to form, forexample, anthracene, phenanthrene, or napthalene ring systems. Exemplaryoptional substituents include lower alkyl, C₃-C₇ cycloalkyl, lowerhaloakyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano,halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. Examples of “aryl” groups include, but arenot limited to, phenyl, 2-naphthyl, 1-naphthyl, and biphenyl, as well assubstituted derivatives thereof.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group which includes C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁-C₆perfluoroalkyl, heteroaryl and aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited to,benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein, attached through a lower alkylene linker,wherein the lower alkylene linker is as defined herein. Examples of“aralkyl” include, but are not limited to benzyl, phenyl propyl,2-pyridyl methyl, 3-isoxazolyl methyl, 5-methyl-3-isoxazolylmethyl, and2-imidazoyly ethyl.

As used herein, the term “aralkylene” refers to an arylene orheteroarylene group, as defined herein, having one attachment through alower alkylene linker, wherein the lower alkylene linker is as definedherein. Examples of “aralkylene” include, but are not limited tobenzylene, phenylpropylene, 2-pyridylmethylene, 3-isoxazolylmethylene,5-methyl-3-isoxazolylmethylene, and 2-imidazolyl ethylene.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen atoms, where N-oxides and sulfur oxides and dioxides arepermissible heteroatom substitutions and may be optionally substitutedwith up to three members selected from a group consisting of loweralkyl, lower haloalkyl, C₃C₇ cycloalkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “heteroaryl” groups used herein includefuran, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline,benzofuran, benzothiophene, indole, indazole, and substituted versionsthereof.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting of:C₁-C₆ alkyl C₁.C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylsulfenyl,C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, C₁-C₆ perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. For polycyclicaromatic ring system diradicals, one or more of the rings may containone or more heteroatoms. Examples of “heteroarylene” used herein arefuran-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered non-aromatic heterocyclic ringbeing saturated or having one or more degrees of unsaturation containingone or more heteroatomic substitutions selected from S. S(O), S(O)₂, O,or N, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower haloalkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. Such a ring may be optionally fused toone or more of another “heterocyclic” ring(s) or cycloalkyl ring(s).Furthermore, such heterocyclyl group optionally includes a C₁-C₄alkylene linker through which it may be attached. Examples of“heterocyclic” include, but are not limited to, tetrahydrofuran, pyran,1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,tetrahydrothiopyran, tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered non-aromatic heterocyclic ring diradical beingunsaturated or having one or more degrees of unsaturation containing oneor more heteroatoms selected from S, SO, SO₂, O, or N, optionallysubstituted with substituents selected from the group which includesC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁₋₆ alkylsulfanyl, C₁-C₆ alkylsulfenyl,C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alky, nitro, cyano,halogen and C₁-C₆ perfluoroalkyl, multiple degrees of substitution beingallowed. Such a ring may be optionally fused to one or more benzenerings or to one or more of another “heterocyclic” rings or cycloalkylrings. Examples of “heterocyclylene” include, but are not limited to,tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and thelike.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkylene and R_(b) is aryl, both as defined above.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfonyl” refers to the groupR_(a)S(O)₂—, where R_(a) is alkyl as defined above.

As used herein, the term “oxo” refers to the group═O.

As used herein, the term “mereapto” refers to the group —SH.

As used herein, the term “carboxy” refers to the group —COO—.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —R_(a)CNwherein R_(a) is C₁-C₃ alkylene as defined above. Exemplary “cyanoalkyl”groups useful in the present invention include, but are not limited tocyanomethyl, cyanoethyl, and cyanopropyl.

As used herein, the term “aminosulfonyl” refers to the group —S(O)₂NH₂.

As used herein, the term “carbamoyl” refers to the group —C(O)N(R_(a))—,wherein R_(a) is any suitable substituent.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂—.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O— whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur, and events that do not occur.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention; for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)), or a salt or physiologically functional derivativethereof) and a solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to water, methanol,ethanol, and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include water, ethanol, and aceticacid. Most preferably the solvent used is water.

The compounds of formula (I) have the ability to crystallize in morethan one form, a characteristic known as polymorphism, and it isunderstood that such polymorphic forms (“polymorphs”) are within thescope of formula (I). Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The compounds of this invention include mixtures ofstereoisomers as well as purified enantiomers or enantiomerically ordiastereomerically enriched mixtures. Also included within the scope ofthe invention are the individual isomers of the compounds represented byformula (I) above as well as any wholly or partially equilibratedmixtures thereof. The present invention also covers the individualisomers of the compounds represented by the formulas above as mixtureswith isomers thereof in which one or more chiral centers are inverted.

It is to be understood that the following embodiments refer to compoundswithin the scope of both formula (I) and formula (II) as defined aboveunless specifically limited by the definition of each formula orspecifically limited otherwise. It is also understood that theembodiments of the present invention described herein, including usesand compositions, although described with reference to formula (I) areapplicable to both formula (I) and formula (II).

As recited above A is the group defined by(Q⁴)_(p)-(Q³)_(n)-(Q²)_(m)-(Q¹)-. In one embodiment, m is 0, n is 0, pis 0, and A is (Q¹)-. In another embodiment, n is 0, p is 0, and A is(Q²)_(m)-(Q¹)-. In a further embodiment, p is 0 and A is(Q³)_(n)-(Q²)_(m)-(Q¹)-. In another embodiment, m is 0, n is 1, p is0,1, or 2, and A is (Q⁴)_(p)-(Q³)-(Q¹)-.

In one embodiment, the compound of formula (I) is a compound of formula(II):

wherein R^(a) is hydrogen or oxo, R^(b) is hydrogen or C₁-C₆ alkyl, andR^(c) is hydrogen or C₁-C₆ alkyl.

In one embodiment, Q¹ is heterocyclyl. In another embodiment, Q¹ isheterocyclylene.

In one embodiment, Q¹ is selected from the group:

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.

In another embodiment, Q¹ is selected from the group:

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.

In another embodiment, Q¹ is selected from the group:

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.

In one embodiment, m is 1 and Q² is OC(O), C(O), N(H)C(O), S(O)₂, orN(H)S(O)₂. In another embodiment, m is 1 and Q² is OC(O) or C(O),preferably OC(O). In an alternative embodiment, m is 1 and Q² isN(H)C(O). In another alternative embodiment, m is 1 and Q² is S(O)₂.

In one embodiment, n is 1 and Q³ is aryl or arylene, heteroaryl orheterarylene, heterocyclyl or heterocyclylene, or aralkyl or aralkylene.

In one embodiment, Q³ is aryl or arylene, preferably selected from thegroup:

In one embodiment, Q³ is aralkyl or aralkylene, preferably selected fromthe group:

In another embodiment, Q³ is heteroaryl or heteroarylene, preferablyselected from the group:

In a further embodiment, Q³ is heterocyclyl or heterocyclylene,preferably selected from the group:

In one embodiment, Q⁴ is methyl, tert-butyl, —CF₃, phenyl, phenoxy,isoxazolyl, thiadiazolyl, thienyl, pyrazinyl, fluoro, chloro, cyano, andp is 1 or 2. In a preferred embodiment, Q⁴ is methyl, tert-butyl, —CF3,phenyl, phenoxy, and fluoro and p is 1 or 2. In a more preferredembodiment, Q⁴ is methyl, and p is 1.

It is understood that Q¹, Q², Q³, and Q⁴ as well as X¹ below areattached to the indicated linking group of Formula (I) or (II) throughthe bond or bonds of Q¹, Q², Q³, and Q⁴, and X¹ having an unfilledvalence and being indicated by

The appropriate attachments are further illustrated in the workingexamples recited below.

As recited above D is O or S. In one embodiment D is S. In a preferredembodiment D is O.

In a preferred embodiment, R is hydrogen.

As recited above Z is the group defined by —(X)_(m)—(X¹). In oneembodiment, m is 0 and Z is —(X¹). In another embodiment, m is 1 and Zis the group defined by —(X)—(X¹).

In one embodiment, X is C(R″)(R′″), wherein R″ is hydrogen or C₁-C₆alkyl, R′″ is hydrogen and C₁-C₆ alkyl, and m is 0, 1, or 2. In anotherembodiment, X is C(H)(R″) where R″ is hydrogen and m is 0, 1, or 2,preferably m is 0 or 1, more preferably m is 0. In another embodiment, Xis C(H)(R″) where R″ is —CH₃ and m is 1.

In one embodiment X¹ is aryl. In a preferred embodiment X¹ is

In one embodiment X¹ is heteroaryl or heterocyclyl. In a preferredembodiment X¹ is selected from the group

Specific examples of compounds of the present invention include thefollowing:

-   (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl    (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4dimethyl-2-oxotetrahydro-3-furanyl (1S)-5-{[(methylamino)    carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl    (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   1-Benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)    pentylcarbamate;-   Benzyl    4,4-dimethyl-2-oxo-3-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)    pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;    3S)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate;-   R)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate;-   1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-Benzyl-4,4-dimethylpyrrolidinyl    1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-Benzoyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-Acetyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(phenylacetyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(5-Isoxazolylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-[(4-methyl-1,2,3-thiadiazol-5-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(3-tert-Butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-4,4-dimethylpyrrolidinyl-   (3S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4Dimethyl-1-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]pyrrolidinyl-   (3S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1,3-Benzodioxol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1-Benzothien-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(2-naphthoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4Dimethyl-1-[(5-methyl-3-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-([1,1′-Biphenyl]-4-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1H-Indol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1H-1,2,3-Benzotriazol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-{[(3-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(4-phenylbutanoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(4-tert-Butylphenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-{[2-(4-pyridinyl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-[(5-methyl-3-phenyl-4-isoxazolyl)carbonyl]pyrrol    idinyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-[(1-methyl-1H-indol-2-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4Dimethyl-1-(3-quinolinylcarbonyl)pyrrolidinyl    1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-([1,1′-Biphenyl]-4-ylacetyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-[(2-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1H-Indol-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(3-pyridinylacetyl)pyrrolidinyl    1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(1H-1,2,4-triazol-3-ylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4Dimethyl-1-[(3-methyl-5-isoxazolyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1H-Indazol-3-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-{[2-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)    pentylcarbamate;-   (3S)-4,4-Dimethyl-1-{[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(4-Fluorophenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)aminocarbonyl)oxy]-1-pyrrolidinecarboxylate;-   [1,1′-biphenyl]-4ylmethyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   Tetrahydro-2-furanyl methyl (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo    {[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   3-Thienylmethyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   (3S)-Tetrahydro-3-furanyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   Benzyl    (4S)-3,3-dimethyl-4[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)    pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   2-Phenylethyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   (1-Phenyl-1H-1,2,3-triazol-4-yl)methyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   2-(2-Oxo-1-pyrrolidinyl)ethyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   Tetrahydro-2H-pyran-2-ylmethyl    (4S)-3,3-dimethyl-4[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   Tetrahydro-3-furanylmethyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   [3-Methyl-5-(5-methyl-isoxazol-3-yl)-4-isoxazolyl]methyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   2-(4Methyl-1,3-thiazol-5-yl)ethyl    (4S)-3,3-dimethyl-4[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   (5-methyl-3-isoxazolyl)methyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   [3-(2,6-Dichlorophenyl)-5-methyl-4-isoxazolyl]methyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   (2-Methyl[1,1′-biphenyl]-3-yl)methyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   [5-(2-Thienyl)-1,2,4-oxadiazol-3-yl]methyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   (3R)-Tetrahydro-3-furanyl    (4S)-3,3-dimethyl-4-[({[(5)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   [1,1′-Biphenyl]-4-yl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   4-Phenoxyphenyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   3-Phenoxyphenyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   2-Naphthyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   4-(1,2,3-Thiadiazol-4-yl)phenyl    (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   Phenyl    3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)    pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;-   (3S)-1-(Anilinocarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(Benzylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;)-   (3S)-4,4-Dimethyl-1-{[(2-phenylethyl)amino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(3-pyridinylcarbonyl)pyrrolidinyl    (15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-{[(3,5-Dimethyl-4-isoxazolyl)amino]carbonyl}-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(Cyclohexylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(4-Cyanoanilino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)—1—phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate;-   (3S)-1-[(5-Fluoro-2-methylanilino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4Dimethyl-1-(4-morpholinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(1-pyrrolidinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-[(Benzoylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-({[(4-methylphenyl)sulfonyl]amino}carbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-4,4-Dimethyl-1-(phenylsulfonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(Benzylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1,3-Benzodioxol-5-ylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)    pentylcarbamate;-   (3S)-1-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-4,4dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;-   (3S)-1-(1,3-Benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate;-   (3S)-4,4-Dimethyl-1-[5-(trifluoromethyl)-1,3,4thiadiazol-2-yl]pyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate;    and-   (3S)-4,4Dimethyltetrahydro-3-furanyl    1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;    or a salt, solvate, or physiologically functional derivative    thereof.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I) or formula (II). Representative salts includethe following salts: acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium, and valerate. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I) or formula (II), as well as salts,solvates and physiological functional derivatives thereof, may beadministered as the raw chemical, it is possible to present the activeingredient as a pharmaceutical composition. Accordingly, the inventionfurther provides pharmaceutical compositions which includetherapeutically effective amounts of compounds of the formula (I) or(II) and salts, solvates and physiological functional derivativesthereof, and one or more pharmaceutically acceptable carriers, diluents,or excipients. The compounds of the formula (I) or (II) and salts,solvates and physiologically functional derivatives thereof, are asdescribed above. The carrier(s), diluent(s) or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Inaccordance with another aspect of the invention there is also provided aprocess for the preparation of a pharmaceutical formulation includingadmixing a compound of the formula (I) or (II), or salts, solvates andphysiological functional derivatives thereof, with one or morepharmaceutically acceptable carriers, diluents or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, of a compound of the formula (I) or (II) depending on thecondition being treated, the route of administration and the age, weightand condition of the patient. Preferred unit dosage formulations arethose containing a daily dose or sub-dose, as herein above recited, oran appropriate fraction thereof, of an active ingredient. Furthermore,such pharmaceutical formulations may be prepared by any of the methodswell known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are prepared by preparing a powder mixture as described aboveand filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methylcellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture is prepared as described aboveby mixing the compound, suitably comminuted, with a diluent or base andoptionally, with a binder such as carboxymethylcellulose, an aliginate,gelatin, or polyvinyl pyrrolidone, a solution retardant such asparaffin, a resorption accelerator such as a quaternary salt and/or anabsorption agent such as bentonite, kaolin or dicalcium phosphate. Thepowder mixture can be granulated by wetting with a binder such as syrup,starch paste, acadia mucilage or solutions of cellulosic or polymericmaterials, and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives; flavor additives suchas peppermint oil, or natural sweeteners, saccharin, or other artificialsweeteners; and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) or (II) and salts, solvates andphysiological functional derivatives thereof, can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) or (II) and salts, solvates andphysiologically functional derivatives thereof may also be delivered bythe use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample; the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns, which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of formula (I) or (II) for the treatment of osteoporosis willgenerally be in the range of 0.1 to 100 mg/kg body weight of recipient(mammal) per day and more usually iii the range of 1 to 10 mg/kg bodyweight per day. Thus, for a 70 kg adult mammal, the actual amount perday would usually be from 70 to 700 mg. This amount may be given in asingle dose per day or more usually in a number (such as two, three,four, five or six) of sub-doses per day such that the total daily doseis the same. An effective amount of a salt or solvate, orphysiologically functional derivative thereof, may be determined as aproportion of the effective amount of the compound of formula (I) or(II) per se. It is envisaged that similar dosages would be appropriatefor treatment of the other conditions referred to above.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in osteoporosis therapy,combination with other osteoporosis therapeutic agents is envisaged.Combination therapies according to the present invention thus comprisethe administration of at least one compound of formula (I) or (II) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other osteoporosis treatment method. Preferably, combinationtherapies according to the present invention comprise the administrationof at least one compound of formula (I) or (II) or a pharmaceuticallyacceptable salt or solvate thereof, or a physiologically functionalderivative thereof, and at least one other osteoporosis treatment agent,preferably a bone building agent. The compound(s) of formula (I) or (II)and the other pharmaceutically active agent(s) may be administeredtogether or separately and, when administered separately, this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) or (II) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect. Theadministration in combination of a compound of formula (I) or (II) orsalts, solvates, or physiologically functional derivatives thereof withother osteoporosis treatment agents may be in combination in accordancewith the invention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one osteoporosis treatment agent isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

A preferred additional osteoporosis treatment agent is a bone building(anabolic) agent. Bone building agents can lead to increases inparameters such as bone mineral density greater than those than can beachieved with anti-resorptive agents. In some cases, such anabolicagents can increase trabecular connectivity leading to greaterstructural integrity of the bone. A combination therapy composed of abone forming agent with an anti-resorptive drug such as a cathepsin Kinhibitor could provide even greater efficacy than treatment with eitheragent alone.

The present invention is directed to methods of regulating, modulating,or inhibiting cathepsin K for the prevention and/or treatment ofdisorders related to an imbalance between bone resorption and formation,which can ultimately lead to fracture. In particular, the compounds ofthe present invention can also be used in the treatment of osteoporosis.Furthermore, the compounds of the present invention can be used toprovide additive or synergistic effects with existing osteoporosistherapies.

The present invention thus also provides compounds of formula (I) or(II) and pharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated by animbalance between bone resorption and formation which can ultimatelyleading to fracture.

The present invention also provides compounds of formula (I) or (II) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders characterized bybone loss or characterized by excessive cartilage or matrix degradation.

The compounds of the present invention are also useful in the treatmentof one or more diseases afflicting mammals that are characterized bypotential involvement of cathepsin K in autoimmune diseases such asrheumatoid arthritis, osteoathritis, neoplastic diseases, parasiticdiseases, and atherosclerosisis.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by an imbalance between boneresorption and formation that can ultimately lead to fracture, whichincludes administering to said subject an effective amount of a compoundof formula (I) or (II) or a pharmaceutically acceptable salt, solvate,or a physiologically functional derivative thereof.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder characterized by bone loss, whichincludes administering to said subject an effective amount of a compoundof formula (I) or (II) or a pharmaceutically acceptable salt, solvate,or a physiologically functional derivative thereof. In a preferredembodiment, the disorder is osteoporosis.

A further aspect of the invention provides a method of treatment of amammal suffering from osteoporosis, which includes administering to saidsubject an effective amount of a compound of formula (I) or (II) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (I) or (II), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by an imbalance between bone resorption and formation thatcan ultimately lead to fracture. In a preferred embodiment, the disorderis osteoporosis.

A further aspect of the present invention provides the use of a compoundof formula (I) or (II), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by bone loss. In a preferred embodiment, the disorder isosteoporosis.

A further aspect of the present invention provides the use of a compoundof formula (I) or (II), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of osteoporosis.

The mammal requiring treatment with a compound of the present inventionis typically a human being.

In another embodiment, therapeutically effective amounts of thecompounds of formula (I) or (II) or salts, solvates or physiologicallyderived derivatives thereof and at least one bone building agent may beadministered in combination to a mammal for treatment of osteoporosis.

The compounds of this invention may be made by a variety of methods,including standard synthetic methods. Any previously defined variablewill continue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

Compounds of general formula (I) or formula (II) may be prepared bymethods known in the art of organic synthesis as set forth in part bythe following synthetic schemes. Generally, the following schemes areillustrated using compounds of formula (II), but it is recognized thatsuch schemes are easily adaptable by the skilled artisan to prepareother compounds of formula (I). It is also recognized that in all of theschemes described below, it is well understood that protecting groupsfor sensitive or reactive groups are employed where necessary inaccordance with general principles of synthetic chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups inOrganic Synthesis, John Wiley

Sons). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art The selection of processes as well as the reaction conditionsand order of their execution shall be consistent with the preparation ofcompounds of formula (I) or (II). Those skilled in the art willrecognize if a stereocenter exists in compounds of formula (I) or (II).Accordingly, the present invention includes all possible stereoisomersand includes not only racemic compounds but the individual enantiomersas well. When a compound is desired as a single enantiomer, it may beobtained by stereospecific synthesis or by resolution of the finalproduct or any convenient intermediate. Resolution of the final product,an intermediate, or a starting material may be effected by any suitablemethod known in the art. See, for example, Stereochemistry of OrganicCompounds by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994).

Compounds of formula (I) and (II), can be prepared according to thesynthetic sequences shown in Schemes I, II, and II, which are furtherdetailed in the Examples section following.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification: g (grams); mg(milligrams); L (liters); ml (milliliters); μL (microliters); psi(pounds per square inch); M (molar); mM (millimolar); h (hour(s)); Hz(Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (roomtemperature); mm (minutes); mp (melting point); TLC (thin layerchromato- graphy); T_(r) (retention time); RP (reverse phase); MeOH(methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA(trifluoroacetic acid); TFAA (trifiuoroacetic anhydride); THF(tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); DME(1,2-dimethoxyethane): DCM (dichloromethane); DCE (dichloroethane); DMF(N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); CDI(1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (aceticacid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzo- triazole);mCPBA (meta-chloroperbenzoic acid; EDC (ethylcarbodiimidehydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmetho-xycarbonyl); DCC (dicycIohcxylcarbodiimide); CBZ (benzyloxycarbonyl); Ac(acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS(trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);DMAP (4-dimethylaminopyridine); Me (methyl); HPLC (high pressure liquidchromatography); BOP (bis(2-oxo-3-oxa- zolidinyl)phosphinic chloride);TBAF (tetra-n-hutylammonium fluoride); Et (ethyl); tBu (tert-butyl).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionswere conducted under an inert atmosphere at room temperature unlessotherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, 8 units). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APIiii spectrometer; high resolution MS wereobtained using a JOEL SX-102A spectrometer. All mass spectra were takenunder electrospray ionization (ESI), chemical ionization (CI), electronimpact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR)spectra were obtained on a Nicolet 510 Fr-IR spectrometer using a 1-mmNaCl cell. All reactions were monitored by thin-layer chromatography on0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light,5% ethanolic phosphomolybdic acid, iodine, iodoplatinate(potassium),permanganate(potassium), or p-anisaldehyde solution. Flash columnchromatography was performed on silica gel (230-400 mesh, Merck).Melting points were determined using a Mel-Temp II apparatus and areuncorrected.

The following examples describe the syntheses of compounds of Formula(I) and (II) as well as intermediates particularly useful in thesynthesis of compounds of Formula (I) and (II):

Example 1 (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(oxo([(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 1a Preparation of benzyl (1S)-1-(hydroxymethyl)pentylcarbamate

A solution of 95.0 mL (95.0 mmol) of 1 M isopropylchloroformate intoluene was added dropwise to a solution of 13.2 mL (95.0 mmol) oftriethylamine and 25.16 g (95.0 mmol) of(2S)-2-{[(benzyloxy)carbonyl]amino}hexanoic acid in 200 mL of anhydroustetrahydrofuran at 0° C. under nitrogen. After 2 h, the resultingmixture was filtered directly into a solution of 7.2 g (190 mmol) ofsodium borohydride in 200 mL water. The resulting mixture was stirredfor 18 h, and then extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium bicarbonate, dried over magnesium sulfate,and concentrated under vacuum. The oily solid was further purified bycolumn chromatography on silica gel, eluting with 4:6 ethylacetate:hexane to afford 9.63 g (40%) of(1S)-1-(hydroxymethyl)pentylcarbamate. ¹H NMR (300 MHz, DMSO-d₆) δ 7.37(m, 5H), 6.97 (d, J=9 Hz, 1H), 5.03 (s, 2H), 4.62 (br s, 1H), 3.46-3.23(m under water peak, 3H), 1.53 (m, 1H), 1.26 (m, 5H), 0.87 (t, J=6 Hz,3H). ES-LCMS m/z 274 (M+Na).

Example 1b Preparation of benzyl (1S)-1-formylpentylcarbamate

A solution of 16.38 g (103 mmol) of sulfur trioxide pyridine complex in130 mL of dimethylsulfoxide was added to a solution of 8.64 g (34.4mmol) of (1S)-1-(hydroxymethyl)pentylcarbamate) and 14.4 mL (103 mmol)of triethylamine in 130 mL of dichloromethane at −10° C. After 1 h, thecold bath was removed, and the reaction mixture was stirred for 18 h. Itwas then poured slowly into a mixture of ice and saturated aqueoussodium chloride. The resulting mixture was extracted with ether. Theether extracts were then washed with 5% aqueous citric acid, andsaturated aqueous sodium chloride. After drying over magnesium sulfate,volatiles were removed under vacuum to afford 7.27 g (85%) of benzyl(1S)-1-formylpentylcarbamate. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H),7.66 (d, J=8 Hz, 1H), 7.33-7.28 (m, 5H), 5.00 (s, 2H), 3.85 (m, 1H),1.65 (m, 1H), 1.40 (m, 1H), 1.27-1.18 (m 4H), 0.79 (m, 3H). ES-LCMS m/z248 (M−H).

Example 1c Preparation of (1R)-α-methylbenzylisonitrile

50 mL of 50% (w/w) aqueous sodium hydroxide was added to a solution of17.5 mL (136 mmol) of (1R)-1-phenylethanamine, 10.8 mL (136 mmol) ofchloroform, and 0.5 g (2.2 mmol) of benzyltriethylammonium chloride in50 mL of dichloromethane. The resulting mixture was stirred for 3 h, andwas then diluted with 100 mL of water and extracted with three 150 mLportions of dichloromethane. The combined extracts were washed with 50mL portions of water and saturated aqueous sodium chloride, dried overmagnesium sulfate, and concentrated under vacuum to afford a darkliquid, which was further purified by column chromatography on silicagel. Elution with dichloromethane afforded 9.86 g (55%) of(1R)-α-methylbenzylisonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ 7.38-7.36 (m,4H), 7.32 (m, 1H), 5.08 (m, 1H), 1.53 (m, 3H).

Example 1d Preparation of(2S)-2-{[(benzyloxy)carbonyl]amino}-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexylbenzoate

To a solution of 7.27 g (29.0 mmol) of benzyl(1S)-1-formylpentylcarbamate in 300 mL of dichloromethane was added 3.8g (29 mmol) of (1R)-α-methylbenzylisonitrile and 3.54 g (29.0 mmol) ofbenzoic acid. The reaction mixture was stirred at room temperature for48 h and diluted with a copious amount of hexanes. The precipitate wascollected by filtration and the filtrate was passed through a silicaplug with 1:9 ethyl ether:dichloromethane. The eluent was concentratedand the residue combined with the collected precipitate to afford 8.7 g(60%) of(2S)-2-{[(benzyloxy)carbonyl]amino}-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexylbenzoate. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=8 Hz, 1H), 8.05 (d, J=7Hz, 2H), 7.62 (t, J=8 Hz, 1H), 7.47 (t, J=8 Hz, 2H), 7.31-7.07 (m_(,)11H), 4.96 (m, 3H), 4.85 (qnt, J=7 Hz, 1H), 4.06 (m, 1H), 1.45-1.05 (m.9H), 0.73 (t, J=7 Hz, 3H). ES-LCMS m/z 525 (M+Na).

Example 1e Preparation of(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide

A mixture of 8.75 g (17.4 mmol) of(2S)-2-{[(benzyloxy)carbonyl]amino}-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexylbenzoate and 6.97 g (174 mmol) of sodium hydroxide in 175 mL of dioxaneand 75 mL of water was heated at reflux for 3 h. Upon cooling to roomtemperature, the reaction mixture was diluted with 100 mL of water andextracted with ethyl acetate. The combined ethyl acetate layers weredried over potassium carbonate and concentrated to afford 4.38 g (95%)of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=8 Hz, 1H), 7.39-7.20 (m,5H), 4.99 (m, 1H), 4.51 (br s, 1H), 3.71 (d, J=3 Hz, 1H), 2.81 (m, 1H),1.50-1.05 (m, 9H), 0.87 (t, 3H). ES-LCMS m/z 265 (M+H).

Example 1f Preparation of (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Phosgene (1.04 mL, 1.93 M, 2.00 mmol) was added dropwise to a solutionof (S)-(+)-pantolactone (130 mg, 1.00 mmol) and quinoline (0.241 mL,2.00 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. under nitrogen.The cold bath was removed, and the mixture was stirred for 18 h at roomtemperature. Volatiles were then removed under vacuum, and the resultingsolid was slurried in anhydrous tetrahydrofuran (4 mL) under nitrogen. Asolution of triethylamine (0.153 mL, 1.10 mmol) and(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide (264 mg, 1.00mmol) in anhydrous tetrahydrofuran was added. The resulting mixture wasstirred for 18 h, and was then partitioned between ethyl acetate (70 mL)and 1 N hydrochloric acid (35 mL). The ethyl acetate layer was washedfurther with two 35 mL portions of 1 N hydrochloric acid, followed bysaturated aqueous sodium chloride (35 mL). After drying over magnesiumsulfate, volatiles were removed to afford(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateas a tan oil (358 mg, 85%).

The tan oil from above (358 mg, 0.850 mmol) was dissolved indichloromethane (15 mL). TEMPO (3 mg, 0.02 mmol), potassium bromide(10.0 mg, 0.085 mmol), and water (0.1 mL) were added, and the resultingmixture was cooled to 0° C. A solution of 5.25% aqueous sodiumhypochlorite (5 mL) containing sodium bicarbonate (60 mg) was then addeddropwise. After 1.3 h, the reaction mixture was diluted with ethylacetate (70 mL), and washed with two 30 mL portions of 1 N hydrochloricacid, followed by saturated sodium chloride (30 mL). The ethyl acetatelayer was then dried over magnesium sulfate, and concentrated undervacuum to a yellow oil, which was further purified by columnchromatography on silica gel. Elution with 25% ethyl acetate in hexanesafforded a colorless oil, from which three 5 mL portions of ether weredistilled. Drying under vacuum afforded(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as acolorless gum (150 mg, 42%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (d, J=8Hz, 1H), 7.97 (d, J=8 Hz, 1H), 7.35-7.22 (m, 5H), 5.00 (m, 1H), 4.83 (m,1H), 4.14 (1/2Abq, J=8 Hz, 1H), 4.05 (1/2Abq, J=8 Hz, 1H), 1.45 (d, J=7Hz, 3H), 1.11 (s, 31H), 1.04 (s, 3H). ES-LCMS m/z 419 (M+H) HRMSC₂₂H₃₀N₂O₆ m/z 441.2002 (M+Na)_(Cal.) 441.2013 (M+Na)_(Obs).

Example 2 (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-5-{[(methylamino)carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 2a Preparation of benzyl(5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate

A solution of 150.0 mL (150.0 mmol) of 1 M isopropylchloroformate intoluene was added dropwise to a solution of 20.9 mL (150.0 mmol) oftriethylamine and 57.06 g (150.0 mmol) of(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxy)carbonyl)amino]hexanoicacid in 500 mL of anhydrous tetrahydrofuran at 0° C. under nitrogen.After 2 h, the resulting mixture was filtered to remove solids, rinsingwith anhydrous tetrahydrofuran (100 mL). The filtrate was then addeddropwise to a stirred solution of 11.35 g (300.0 mmol) of sodiumborohydride in 500 mL water, cooled in an ice bath. The cold bath wasremoved, and the resulting mixture was stirred for 18 h. It was thendiluted with ethyl acetate (800 mL) and saturated aqueous sodiumbicarbonate (300 mL). The two layers were separated, the aqueous layerwas extracted with two 250 mL aliquots of ethyl acetate, and theextracts were combined with the original ethyl acetate layer. Thecombined ethyl acetate phase was washed with three 100 ml portions ofsaturated aqueous sodium bicarbonate, dried over magnesium sulfate, andconcentrated under vacuum. The yellow oil was further purified by columnchromatography on silica gel, eluting with 4:1 ethyl acetate:hexane toafford 37.70 g (68%) of benzyl(5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate. ¹H NMR (300MHz, DMSO-d₆) δ 7.43-7.30 (m, 5H), 7.25 (t, J=5 Hz, 1H), 6.45 (d, J=8Hz, 1H), 5.02 (s, 2H), 4.57 (br s, 1H), 3.35-3.29 (m overlapping waterpeak, 2H), 3.26-3.16 (m, 1H), 3.04-2.93 (m, 2H), 1.39 (s, 9H), 1.57-1.16(m, 6H). ES-LCMS m/z 389 (M+Na).

Example 2b Preparation of(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal

A solution of sulfur trioxide pyridine complex (53.0 g, 333 mmol) indimethylsulfoxide (300 mL) was added to a solution of benzyl(5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate (8.64 g, 34.4mmol) and triethylamine (14.4 mL, 103 mmol) in dichloromethane (130 mL)at 0° C. The cold bath was removed, and the reaction mixture was stirredfor 23 h. It was then poured slowly into a mixture of ice and saturatedaqueous sodium chloride (1000 mL). The resulting mixture was extractedwith three 600 mL portions of ether. The ether extracts were thencombined, washed with three 150 mL portions of saturated aqueous sodiumchloride, and concentrated to 1200 mL The concentrated ether phase wasfurther washed with three 200 mL aliquots of 5% aqueous citric acid, anda 200 mL portion of saturated aqueous sodium chloride. After drying overmagnesium sulfate, volatiles were removed under vacuum to afford(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal(37.58 g. 93%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (s, 1H), 7.46-7.23 (m,6H), 5.02 (s, 2H), 3.85-3.75 (m, 1H), 3.07-2.93 (m, 2H), 1.77-1.60 (m,1H), 1.56-1.23 (m, 5H), 1.41 (s, 9H).

Example 2c Preparation of(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexylbenzoate

A solution of (1R)-α-methylbenzylisonitrile (9.6 g, 73 mmol) indichloromethane (200 mL) was added to a solution of(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanalin dichloromethane (355 mL, 0.206 M, 73.0 mmol). Benzoic acid (8.9 g, 73mL) was then added, and the resulting solution was stirred at roomtemperature for 18 h. Volatiles were then removed under vacuum, and theresulting yellow solid was further purified by column chromatography onsilica gel. Elution with a gradient of 5-15% ether in dichloromethaneafforded an oil, which was precipitated from hot ether with hexane toprovide(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexylbenzoate as a white solid (28.03 g, 620/a), after drying under vacuum.¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (d, J=8 Hz) and 8.58 (d, J=8 Hz) total1H, 8.15 (d, J=7 Hz), 8.09 (d, J=8 Hz), and 7.97 (d, J=7 Hz) total 2H,7.72-7.67 (m, 1H); 7.68-7.60 (m, 2H); 7.44-7.18 (m, 10 H); 6.86 (d, J=10Hz, 1H); 5.08-4.89 (m, 3H); 4.11-3.98 (m, 1H); 3.042.89 (m, 2H);1.50-1.13 (m, 18H). ES-LCMS m/z 618 (M+H).

Example 2d tert-butyl(1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

(2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexylbenzoate (28.0 g, 45.0 mmol) was dissolved in dioxane (200 mL), and asolution of lithium hydroxide (2.47 g, 174 mmol) in water (100 mL) wasadded. The resulting mixture was stirred for 24 h at room temperature.It was then diluted with ethyl acetate (500 mL), and washed with 1Nhydrochloric acid (300 mL). The aqueous layer was back-extracted withtwo 100 mL portions of ethyl acetate. The extracts were then combinedwith the original ethyl acetate layer, washed with three 200 mL aliqoutsof saturated aqueous sodium bicarbonate, followed by saturated aqueoussodium chloride (100 mL), and dried over magnesium sulfate. Volatileswere then removed under vacuum to afford tert-butyl(3S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateas a waxy light yellow solid (25.61 g, quantitative crude yield). ¹H NMR(300 MHz, DMSO-d₆) δ 7.98-7.88 (m, 1H); 7.68-7.63 (m) and 7.49-7.42 (m)total 1H, 7.35-7.10 (m, 10H); 6.31 (d, J=9 Hz) and 6.02 (d, J=9 Hz)total 1H, 5.62-5.53 (br s) and 5.53-5.42 (br s) total 1H, 4.94 (s, 2H),4.91-4.83 (m, 1H); 3.87 (br s) and 3.79 (br s) total 1H, 3.72-3.58 (m,1H); 2.99-2.76 (m, 2H); 1.47-1.10 (m, 18H). ES-LCMS m/z 514 (M+H).

Example 2e Preparation of tert-butyl(1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

A slurry of palladium on carbon (1.5 g, 10% w/w) in water (3 mL) wasadded to a solution of tert-butyl(1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(15.28 g, 29.70 mmol) in ethanol (200 mL). The resulting slurry wasstirred vigorously under a hydrogen atmosphere (45 psi) at 50° C. for 18h. Catalyst was then filtered off, rinsing with ethanol (400 mL).Concentration of the filtrate under vacuum afforded tert-butyl(1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateas a colorless oil that crystallized upon standing under vacuum (10.52g, 93%). ¹H NMR (300 MHz, DMSO-d₆) δ8.15 (d, J=8 Hz) and 8.08 (d, J=8Hz) total 1H, 7.90-7.87 (m, ca 1H); 7.87-7.28 (m, 4H); 7.25-7.20 (m,1H); 6.51 (d, J=9 Hz) and 6.17 (d, J=9 Hz) total 1H; 4.99-4.92 (m, 1H);3.96 (d, J=4 Hz) and 3.90 (d, J=3 Hz) total 1H, 3.80-3.69 (m, 1H);2.68-2.64 (m) and 2.53-2.57 (m) total 1H, 1.53-1.23 (m, 18H). ES-LCMSm/z 380 (M+H).

Example 2f Preparation of tert-butyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate

Methylisocyanate (0.472 mL, 8.00 mmol) was added to a slurry oftert-butyl(3S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(3.03 g, 8.00 mmol) at 0° C. in anhydrous tetrahydrofuran (60 mL) undernitrogen. The mixture was stirred at 0° C. for 1 h, during which timeall solids dissolved. The cold bath was then removed, and the solutionwas stirred overnight Volatiles were removed under vacuum, and theresulting foam was further purified by column chromatography on silicagel. Elution with a gradient from 50% to 75% acetone in hexane affordedtert-butyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamateas a white solid after drying under vacuum (3.00 g, 86%). ¹H NMR (300MHz, DMSO-d₆) δ 8.06-8.01 (m, 1H); 7.38-7.18 (m, 5H); 6.40 (d, J=10 Hz)and 6.08 (d, J=9 Hz) total 1H, 5.86-5.75 (m, 1H); 5.71-5.51 (m, 2H);5.01-4.91 (m, 1H); 3.94 (br s) and 3.87 (br s) total 1H, 3.79-3.64 (m,1H); 3.01-2.81 (m, 2H); 2.54 (d, J=5 Hz, 3H); 1.52-1.16 (m, 18H).ES-LCMS m/z 437 (M+H).

Example 2g Preparation of(3S)-3-amino-2-hydroxy-7-{[(methylamino)carbonyl]amino}-N-[(1R)-1-phenylethyl]heptanamidehydrochloride

A solution of tert-butyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate(2.86 g, 6.55 mmol) in ethyl acetate (200 mL) and methanol (50 mL) wascooled to 0° C., and saturated with hydrogen chloride by bubblinganhydrous hydrogen chloride through it for 7 min. The resulting solutionwas stirred for 1.5 h. Volatiles were then removed, and the resultingoil was dried further under vacuum to afford(3S)-3-amino-2-hydroxy-7-{[(methylamino)carbonyl]amino}-N-[(1R)-1-phenylethyl]heptanamidehydrochloride as a solid foam (2.74 g, quantitative yield) containingethanol (0.53 eq based on integration of signals in the ¹H NMRspectrum). ¹H NMR (300 MHz, DMSO-d₆) δ 8.56 (d, J=8 Hz) and 8.45 (d, J=8Hz) total 1H, 8.14 (br s) and 7.95 (br s) total 3H; 7.39-7.18 (m, 5H);7.16-6.50 (br s, ca 3H); 5.02-4.91 (m, 1H); 4.30 (br s) and 4.09 (d, J=5Hz) total 1H, 3.38-3.17 (m, 1H); 3.02-2.82 (m, 2H); 2.55 (s, 3H);1.63-1.15 (m, 6H); 1.44 (s, 3H). ES-LCMS m/z 337 (M+H).

Example 2h Preparation of (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanylchloridocarbonate

A solution of (S)-(+)-pantolactone (651 mg, 5.00 mmol) and 2,6-lutidine(0.641 mL, 5.50 mmol) in ether (15 mL) was stirred in the presence ofpowdered 4 A molecular sieves in a heat dried flask under nitrogen.After 30 min, the mixture was allowed to settle, and the supernatant wascannulated onto a solution of phosgene in toluene (15.5 mL, 1.93 M, 30.0mmol) under nitrogen at 0° C. The resulting mixture was stirred for 2 hand was then filtered through celite under nitrogen. Volatiles wereremoved under vacuum, and two 15 mL portions of anhydrous ether weredistilled from the residue under vacuum to afford(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl chloridocarbonate as ayellow oil, a small portion of which was characterized by NMR. The restwas dissolved in dichloromethane (5 mL) to make a 1 M solution. ¹H NMR(400 MHz, CDCl₃) δ 5.21 (s, 1H), 4.03 (1/2Abq, J=9 Hz, 1H), 3.97(1/2Abq, J=9 Hz, 1H), 1.22 (s, 3H), 1.12 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 169.90 (C), 150.70 (C), 81.23 (CH), 76.04 (CH₂), 40.35 (C),22.91 (CH₃), 19.72 (CH₃).

Example 2i Preparation of (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate

A solution of(3S)-3-amino-2-hydroxy-7-{[(methylamino)carbonyl]amino}-N-[

-   R)-1-phenylethyl]heptanamide hydrochloride (198 mg, 0.500 mmol) in    methanol (5 mL) was cooled to 0° C. under nitrogen. Triethylamine    (0.153 mL, 1.10 mmol) was then added, followed by a solution of    (3S)-4,4dimethyl-2-oxotetrahydro-3-furanyl chloridocarbonate in    dichloromethane (0.60 mL 1 M, 0.60 mmol). The reaction mixture was    allowed to warm slowly to room temperature, and was stirred for    15 h. Volatiles were removed under vacuum, and the resulting oil was    dissolved in ethyl acetate (50 mL). This solution was washed with    three 15 mL portions of 1 N hydrochloric acid, and the washes were    back-extracted with three 35 mL aliquots of ethyl acetate. The    extracts were combined with the original ethyl acetate solution, and    the resulting solution was dried over magnesium sulfate.    Concentration under vacuum afforded a gummy solid, which was further    purified by column chromatography on silica gel. Elution with 7%    methanol in chloroform afforded    (3S)-4,4dimethyl-2-oxotetrahydro-3-furanyl    (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate    as a colorless glass (180 mg, 73%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.07    (d, J=9 Hz, 1H); 7.41-7.22 (m, 5H); 6.95 (d, J=9 Hz, 1H); 5.89-5.74    (m, 1H); 5.39 (s) and 5.36 (s) total 1H, 4.99-4.90 (m, 1H); 4.14    (1/2Abq, J=9 Hz, 1H); 4.03 (1/2Abq, J=9 Hz, 1H); 3.95-3.90 (m, 1H);    3.86-3.73 (m, 1H); 3.01-2.85 (m, 2H); 2.55 (part of d overlapping    DMSO, 3H); 1.52-1.17 (m, 9H); 1.12 (s) and 1.09 (s) total 1H,    1.01 (s) and 0.99 (s) total 1H. ES-LCMS m/z 493 (M+H).

Example 2j Preparation of (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-5-{[(methylamino)carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of oxalylchloride (0.058 mL, 0.67 mmol) in anhydrousdichloromethane (2 mL) was cooled to −60° C. under nitrogen. Anhydrousdimethylsulfoxide (0.095 mL, 1.34 mmol) was then added dropwise, and theresulting solution was stirred for 10 min. A solution of(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate(150 mg, 0.30 mmol) in dichloromethane (3 mL) was then added. After 15min, triethylamine (0.212 mL, 1.52 mmol) was added to the reactionmixture, which was kept cold for 2 min. and then allowed to warm to roomtemperature. After 40 min, the reaction mixture was subjected directlyto column chromatography on silica gel. Elution with 10% acetone inethyl acetate afforded (3S)-4,4ddimethyl-2-oxotetrahydro-3-furanyl(1S)-5-{[(methylamino)carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamateas a colorless gum after drying under vacuum (82 mg, 56%). ¹H NMR (300MHz, DMSO-d₆) δ 9.26 (d, J=8 Hz, 1H); 7.99 (d, J=8 Hz, 1H); 7.40-7.33(m, 4H); 7.31-7.23 (m, 1H); 5.92-5.84 (m, 1H); 5.71-5.63 (m, 1H); 5.40(s, 1H); 5.08-4.96 (m, 1H); 4.85-4.78 (m, 1H); 4.16 (1/2Abq, J=8 Hz,1H); 4.06 (1/2Abq, J=8 Hz, 1H); 3.042.91 (m, 2H); 2.55 (part of doverlapping DMSO, 3H); 1.74-1.61 (m, 1H); 1.46 (d, J=7 Hz, 1H);1.45-1.29 (m, 5H); 1.12 (s, 1H); 1.05 (s, 1H). ES-LCMS m/493 (M+H) HRMSC₂₄H₃₄N₄O₇ m/491.2505 (M+H)ca. 491.2490 (M+H)_(Obs).

Example 3 (4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl(1S)-7-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 3a Preparation of dimethyl (2R,3S)-2-ethyl-3-hydroxymethylbutanedioate

To a −78° C. solution of 9.09 mL (65 mmol) of diisopropylamine in 100 mLof tetrahydrofuran was added dropwise 40.5 mL (65 mmol) of 1.6 M n-butyllithium in hexanes. The solution was allowed to warm to 0° C. brieflybefore being cooled to −78° C. To the solution was added 4.09 mL (30.9mmol) of dimethyl (S)-(−)-malate dropwise and the resulting solution wasallowed to warm to room temperature. After 30 min at room temperature,it was cooled to −78° C. before 2.3 mL (37.1 mmol) of methyl iodide wasadded dropwise. The solution was allowed to warm to room temperature,and was stirred for 18 h. It was then poured onto a mixture of ether,ice water, and 9.27 mL of acetic acid. The resulting mixture wasextracted with ether, and the extracts were combined, washed withsaturated sodium bicarbonate and brine, dried over magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with 3:7 ethyl acetate:hexanes toafford 1.04 g (5.9 mmol) of dimethyl(2S,3S)-2-hydroxy-3-methylbutanedioate.

A solution of 1.74 mL (12.4 mmol) of diisopropylamine in 20 mL oftetrahydrofuran was cooled to −78° C. before 7.75 mL (12.4 mmol) of 1.6M n-butyl lithium in hexanes was added dropwise. The solution wasallowed to warm to 0° C. briefly before being cooled to −78° C. Asolution of dimethyl (2S,3S)-2-hydroxy-3-methylbutanedioate in 1 mL oftetrahydrofuran was then added dropwise. The reaction mixture wasallowed to warm to −10° C., and was stirred for 45 min before beingcooled to −78° C. To the reaction mixture was added 0.52 mL (6.5 mmol)of ethyl iodide dropwise. The reaction mixture was then stirred for 1 hbefore being allowed to warm to room temperature. After 18 h, thereaction mixture was poured onto a mixture of ether, ice water, and 1.8mL of acetic acid. The mixture was extracted with ether, and thecombined extracts were washed with saturated sodium bicarbonate andbrine, dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica chromatography eluting with3:7 ethyl acetate:hexanes to afford 430 mg (6.8%) of dimethyl(2R,3S)-2-ethyl-3-hydroxy-2-methylbutanedioate. ¹H NMR (300 MHz,DMSO-d₆) δ 5.73 (s, 1H), 4.28 (s, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 1.66(m, 1H), 1.38 (m, 1H), 0.76 (t, J=7 Hz, 3H).

Example 3b Preparation of(3S,4S)-4-ethyl-3-hydroxy-4-methyldihydro-2(3H)-furanone

To a solution of 430 mg (2.1 mmol) of dimethyl(2R,3S)-2-ethyl-3-hydroxy-2-methylbutanedioate in 5 mL of methanol wasadded a solution of 0.29 g (4.4 mmol) of potassium hydroxide (>85%) in0.5 mL of water and 1 mL of methanol. The reaction mixture was stirredfor 96 h and diluted with ether. The ether layer was removed and theaqueous phase was washed with ether. The aqueous phase was thenacidified to pH=2 with 1N HCl before being extracted with ether. Thecombined ether extracts were dried over magnesium sulfate andconcentrated under reduced pressure to leave 310 mg (1.6 mmol) of anoil. The oil was dissolved in 15 mL of tetrahydrofuran and the solutionwas cooled to −40° C. before 8.8 mL (8.8 mmol) of 1M lithiumtriethylborohydride in tetrahydrofuran was added dropwise. The reactionmixture was allowed to warm to room temperature and was stirred for 18h. It was then cooled to −10° C. and 5 drops of water were added. Themixture was diluted with ether, and 1N HCl was added until the pH of theaqueous layer reached a value of 2. The mixture was extracted withether. The combined ether layers were diluted with toluene before beingconcentrated under reduced pressure. The residue was subjected to silicagel chromatography eluting with 4:6 ethyl acetate:hexanes. Appropriatefractions were concentrated under reduced pressure and the residue waspassed through a silica plug with ether. The filtrate was concentratedunder reduced pressure to afford 120 mg (40%) of(3S,4S)-4-ethyl-3-hydroxy-4methyldihydro-2(3H)-furanone. ¹H NMR (300MHz, DMSO-d₆) δ 5.99 (s, 1H), 4.12 (s, 1H), 4.10 (d, J=9 Hz, 1H), 3.88(d, J=9 Hz, 1H), 1.33 (m, 2H), 1.05 (s, 3H), 0.84 (t, J=7 Hz, 3H).ES-LCMS m/z 145 (M+H).

Example 3c Preparation of(3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-0.1-phenylethyl]amino}ethyl)pentylcarbamate

To a solution of 120 mg (0.83 mmol) of(3S,4S)-4-ethyl-3-hydroxy-4-methyldihydro-2(3H)-furanone and 0.11 mL(0.92 mmol) of 2,6-lutidine in 3 mL of ether was added 180 mg of 4 Åmolecular sieves. The mixture was stirred for 45 min and let settle for30 min. The supernatant was transferred via cannula to a solution ofphosgene (2.6 mL, 1.93 M in toluene, 5.0 mmol) in 10 mL of ether at 0°C. After 30 min, the reaction mixture was allowed to warm to roomtemperature. It was stirred for 2 h, and then filtered through a celiteplug with ether. The filtrate was concentrated to 1 mL, and added to asolution of 220 mg (0.83 mmol) of(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide and 0.13 mL(0.91 mmol) of triethylamine in 2 mL of tetrahydrofuran. The reactionmixture was stirred for 18 h at room temperature. It was then dilutedwith ethyl acetate, washed with 1N HCl, and dried over magnesium sulfatebefore being concentrated. The residue was purified by silica gelchromatography, eluting with 1:1 ethyl acetate:hexanes to afford 170 mg(47%) of (3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate.¹H NMR (300 MHz, DMSO-d₆) δ 7.99 (d, J=8 Hz, 1H), 7.23-7.29 (m, 5H),7.16 (m, 1H), 6.85 (d, J=9 Hz, 1H), 5.53 (s, 1H), 4.87 (m, 1H), 4.10 (d,J=9 Hz, 1H), 3.98 (d, J=9 Hz, 1H), 3.83 (s, 1H), 3.73 (m, 1H), 1.15-1.55(m, 11H), 0.97 (s, 3H), 0.76-0.81 (m, 6H). ES-LCMS m/z 435 (M+H).

Example 3d Preparation of(4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

To a −60° C. solution of 0.062 mL (0.71 mmol) of oxalyl chloride in 1 mLof dichloromethane was added 0.10 mL (1.4 mmol) of dimethylsulfoxidedropwise. After 2 min. a solution of 140 mg (0.32 mmol) of(3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatein 1 mL of dichloromethane was added. The mixture was stirred for 10 minbefore 0.22 mL (1.6 mmol) of triethylamine was added. The reactionmixture was allowed to warm to room temperature and was stirred for 15min before being poured directly onto a silica gel column. The columnwas eluted with 2:3 ethyl acetate:hexanes to afford 111 mg (80%) of(3S)-1-benzyl-4,4dimethylpyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. ¹H NMR (300MHz, 80° C., DMSO-d₆) δ 8.95 (m, 1H), 7.77 (m, 1H), 7.21-7.40 (m, 1H),5.36 (d, J=6 Hz, 1H), 5.03 (m, 1H), 4.85 (m, 1H), 4.18 (m, 1H), 4.05 (m,1H), 1.23-1.88 (m, 11H), 1.10 (s, 1H), 0.89 (m, 6H). ES-LCMS m/z 433(M+H); HRMS C₂₃H₃₂N₂O₆ m/z 487.2420 (M+Na+MeOH)⁺ _(Cal); 487.2411 (M+Na⁺MeOH)⁺ _(Obs).

Example 41-Benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 4a Preparation of1-benzyl-3-hydroxy-4,4-dimethyl-2-pyrrolidinone

A solution of (S)-(+)-pantolactone (2.60 g, 20.0 mmol) and benzylaminehydrochloride (10 g, 70 mmol) in benzylamine (60.0 mL, 550 mmol) wasstirred at 180° C. for 3 d. After cooling, the mixture was poured intodichloromethane (200 mL). The resulting mixture was filtered, and thefiltrate was washed with three 150 mL portions of 1 N hydrochloric acid,followed by 100 mL of saturated aqueous sodium chloride. After dryingover magnesium sulfate, the solution was concentrated to a tancrystalline solid, which was further purified by column chromatographyon silica gel. Elution with a gradient of 3-5% methanol in chloroformseparated the desired product from the intermediate,N-benzyl-2,4dihydroxy-3,3-dimethylbutanamide, which was isolated as acolorless oil (1.28 g, 27%). The desired product was further purified bycolumn chromatography on silica gel, eluting with 2:1 to 1:1hexane:ethyl acetate to afford1-benzyl-3-hydroxy-4,4-dimethyl-2-pyrrolidinone as a white crystallinesolid (1.501 g, 34%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.43-7.12 (m, 5H),5.52 (br s, 1H), 4.39 (1/2Abq, J=15 Hz, 1H), 4.25 (1/2Abq, J=15 Hz, 1H),3.78 (br s, 1H), 2.89 (1/2Abq, J=10 Hz, 1H), 2.80 (1/2Abq, J=9 Hz, 1H),1.01 (s, 3H), 0.79 (s, 3H). ES-LCMS m/z 220 (M+H).

Example 4b Preparation of 1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinylchloridocarbonate

1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl chloridocarbonate (281 mg,quantitative yield) was obtained as an oil from1-benzyl-3-hydroxy-4,4-dimethyl-2-pyrrolidinone (219 mg, 1.00 mmol)following the procedure outlined in example 2h. ¹H NMR (400 MHz, CDCl₃)δ 7.32-7.15 (m, 5H), 5.12 (s, 1H), 4.46 (1/2Abq, J=14 Hz, 1H), 4.34(1/2Abq, J=15 Hz, 1H), 2.95 (1/2Abq, J=10 Hz, 1H), 2.89 (1/2Abq, J=10Hz, 1H), 1.13 (s, 3H), 0.97 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) 6167.58(C), 151.05 (C), 135.39 (C), 129.08 (CH), 128.24 (CH), 84.92 (CH), 56.48(CH₂), 47.22 (CH₂), 37.88 (C), 25.24 (CH₃), 21.12 (CH₃).

Example 4c Preparation of1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatewas obtained as a colorless film (146 mg, 92%) from1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl chloridocarbonate (98 mg,0.40 mmol) and (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide(82 mg, 0.31 mmol) following the procedure outlined in example 2i,except that the reaction mixture was not cooled to 0° C. The titlecompound was purified by column chromatography on silica gel, elutingwith 3% methanol in chloroform. ¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (m,1H); 7.41-7.24 (m, 10); 6.80 (m, 1H); 5.58 (m, 1H); 5.07 (s), 5.05 (s),and 5.04 (s) total 1H, 4.97 (m, 1H); 4.45 (m, 1H); 4.30 (m, 1H); 3.91(m, 1H); 3.80 (m, 1H); 3.12-3.06 (m, 1H); 2.92-2.85 (m, 1H); 1.60-1.20(m, 12H); 1.08 (s) and 1.06 (s) total 3H, 0.90-0.73 (m, 6H). ES-LCMS m/z510 (M+H).

Example 4d Preparation of1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a cloudy gum (105 mg, 71%) containing ethyl acetate(0.67 eq based on integration of signals in the ¹H NMR spectrum) from1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(133 mg, 0.260 mmol) following the procedure outlined in example 2j. Thetitle compound was purified by column chromatography on silica gel,eluting with a gradient of 33-40% ethyl acetate in hexane. ¹H NMR (300MHz, DMSO-d₆) δ 9.16 (m, 1H); 7.86 (d, J=8 Hz) and 7.76 (d, J=7 Hz)total 1H, 7.32-7.15 (m, 10H); 4.98 (s) and 4.96 (s) total 1H, 4.95-4.88(m, 1H); 4.82-4.71 (m, 1H); 4.42 (m, 1H); 4.22 (m, 1H); 3.01 (m, 1H);2.83 (m, 1H); 1.64-1.52 (m, 1H); 1.40-1.09 (m, 8H); 1.03 (s), 1.01 (s),and 0.99 (s) total 3H, 0.84-0.72 (m, 6H). ES-LCMS m/z 508 (M+H) HRMSC₂₉H₃₇N₃O₅ m/z 508.2811 (M+H)_(Cal.) 508.2827 (M+H)_(Obs).

Example 5 Benzyl4,4-dimethyl-2-oxo-3-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

Example 5a Preparation of 3-hydroxy-4,4-dimethyl-2-pyrrolidinone

A solution of (S)-(+)-pantolactone (1.30 g, 10.0 mmol) in ammoniumhydroxide (50 mL, 28%) and ethanol (40 mL) was stirred in a sealedpressure reactor at 230° C. for 23 h. After cooling to room temperature,the reaction mixture was diluted with dichloromethane (60 mL) and water(30 mL). 1 N hydrochloric acid was added until the pH of the aqueouslayer reached a value of 2, and the two phases were separated. Theaqueous layer was extracted with three 30 mL portions ofdichloromethane, and the dichlormethane layers were combined. They werethen washed with aqueous saturated sodium chloride (30 mL), dried overmagnesium sulfate, and concentrated to afford impure product (152 mg).The aqueous layer was then made neutral by the addition of 5 N aqueoussodium hydroxide, and volatiles were removed under vacuum. The residuewas slurried in 10% methanol in chloroform, and passed over a shortsilica gel column, eluting with the same system. The filtrate wasconcentrated, and the residue was combined with the impure productobtained from extraction of the aqueous layer. This impure product wasfurther purified by column chromatography on silica gel. Elution with10% methanol in chloroform afforded3-hydroxy-4,4-dimethyl-2-pyrrolidinone as a white crystalline solid(0.670 g, 52%) after drying under vacuum. ¹H NMR (300 MHz, DMSO-d₆) δ7.56 (br s, 1H), 5.33 (d, J=6 Hz, 1H), 3.66 (d, J=6 Hz, 1H), 2.93-2.83(m, 2H), 1.09 (s, 3H), 0.90 (s, 3H). ES-LCMS m/z 130 (M+H).

Example 5b Preparation of3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-pyrrolidinone

tert-Butyldimethylsilyl trifluoromethanesulfonate (0.810 ml, 3.45 mmol)was added to a mixture of 3-hydroxy-4,4dimethyl-2-pyrrolidinone (405 mg,3.1 mmol) and triethylamine (0.481 mmol, 3.45 mmol) in anhydrousdichloromethane (20 mL) at 0° C. under nitrogen. The reaction mixturewas allowed to warm to room temperature, and was stirred for 18 h. Acatalytic portion of 4-(dimethylamino)pyridine was added, and themixture was stirred for 5 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.470mL, 3.13 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate(0.360 ml, 1.61 mmol) were then added. After an additional 16 h, a thirdportion of tert-butyldimethylsilyl trifluoromethanesulfonate was added(0.360 ml, 1.61 mmol). The reaction mixture was then stirred for afurther 7.5 h, before being diluted with dichloromethane (75 mL). It wasthen washed with two 30 mL portions of 1N hydrochloric acid. The washeswere combined and back-extracted with dichloromethane (30 mL). Thedichloromethane layers were then combined, washed with saturated aqueoussodium chloride (20 mL), dried over magnesium sulfate, and concentratedto a tan oil. Further purification of this oil by column chromatographyon silica gel, eluting with a gradient of 20-50% ethyl acetate in hexaneafforded 3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-pyrrolidinoneas a colorless oil that crystallized upon standing (362 mg, 48%). ¹H NMR(300 MHz, DMSO-d₆) δ7.63 (br s, 1H), 3.85 (s, 1H), 2.96-2.84 (m, 2H),1.08 (s, 3H), 0.92 (s, 3H), 0.91 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H).ES-LCMS m/z 244 (M+H).

Example 5c Preparation of benzyl3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate

Sodium hydride (39 mg, 0.97 mmol) was added to a solution of3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-pyrrolidinone (214 mg,0.880 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen at 0° C.After 10 min, benzyl chloroformate (0.200 mL, 1.32 mmol) was added, andthe mixture was allowed to warm to room temperature. After 24 h, themixture was diluted with saturated aqueous sodium chloride (30 mL) anddichloromethane (30 mL). Hydrochloric acid (10 mL, 1 N) was then added,and the two phases were separated. The aqueous layer was extracted withdichloromethane (35 mL), and the dichloromethane layers were combined.After washing with saturated aqueous sodium chloride, they were driedover magnesium sulfate and concentrated to a tan oil, which was furtherpurified by column chromatography on silica gel. Elution with 10:1hexane:ethyl acetate afforded benzyl3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylateas a colorless oil (312 mg, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.47-7.34(m, 5H), 5.27 (1/2Abq, J=13 Hz, 1H), 5.21 (1/2Abq, J=13 Hz, 1H), 4.24(s, 1H), 3.50 (1/2Abq, J=11 Hz, 1H), 3.38 (1/2Abq, J=11 Hz, 1H), 1;12(s, 3H), 0.92 (s, 9H), 0.90 (s, 3H), 0.13 (s, 3H), 0.10 (s, 3H). ES-LCMSm/z 378 (M+H).

Example 5d Preparation of benzyl3-hydroxy-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate

A solution of tetrabutylammonium fluoride in anhydrous tetrahydrofuran(1.1 mL, 1M, 1.1 mmol) was added to a solution of3-{[tert-butyl(dimethyl)silyl]oxy}-4,4dimethyl-2-oxo-1-pyrrolidinecarboxylate(202 mg, 0.54 mmol) in anhydrous tetrahydrofuran (2 mL) under nitrogen.After 45 min, the reaction mixture was subjected directly to columnchromatography. Elution with 50% ethyl acetate in hexane afforded benzyl3-hydroxy-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate as an oil thatsolidified upon standing (133 mg, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ7.47-7.36 (m, 1H), 5.88 (d, J=6 Hz, 1H), 5.24 (s, 2H), 3.99 (d, J=6 Hz,1H), 3.48 (1/2Abq, J=10 Hz, 1H), 3.35 (1/2Abq, J=10 Hz, 1H), 1.11 (s,3H), 0.89 (s, 3H). ES-LCMS m/z 378 (M+H).

Example 5e Preparation of benzyl3-[({[(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentyl]amino}carbonyl)oxy]-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate

Benzyl3-[({[(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentyl]amino}carbonyl)oxy]-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylatewas prepared from benzyl3-hydroxy-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate and(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide following theprocedure outlined in example 3c (56% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 8.15 (m, 1H), 7.07-7.40 (m, 10H), 5.17 (m, 1H), 5.80 (m, 1H), 5.53 (m,1H), 5.17 (m, 2H), 4.89 (m, 1H), 3.83 (m, 1H), 3.71 (m, 1H), 3.54 (m,1H), 3.44 (s, 1H), 0.75-1.45 (m, 18H). ES-LCMS m/z 554 (M+H).

Example 5f Preparation of benzyl4,4dimethyl-2-oxo-3-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

Benzyl4,4-dimethyl-2-oxo-3-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylatewas prepared from benzyl3-[({[(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentyl]amino}carbonyl)oxy]-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylatefollowing the procedure outlined in example 3d (45% yield). ¹H NMR (300MHz, DMSO-d₆) δ 9.20 (m, 1H), 7.90 (m, 1H), 7.15-7.43 (m, 10H), 5.21 (s,1H), 4.96 (m, 1H), 4.80(m, 1H), 3.54 (s, 2H), 3.25 under water peak (m,1H), 0.75-1.80 (m, 18H). ES-LCMS m/z 574 (M+Na); HRMS C₃₀H₃₇N₃O₇ m/z574.2529 (M+Na)⁺ _(Cal); 574.2516 (M+Na)⁺ _(Obs).

Example 6

(3S)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand (3R)-4,4-dimethyl-2-oxopyrrolidinyl(3S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

Example 6a Preparation of4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

A solution of 120 mg (0.22 mmol) of benzyl3-[({[(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentyl]amino}carbonyl)oxy]-4,4dimethyl-2-oxo-1-pyrrolidinecarboxylatein 5 mL of tetrahydrofuran was stirred in the presence of 15 mg of 10%Pd/C under a hydrogen atmosphere (50 psi) for 18 h. The catalyst wasfiltered off over celite and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 3:2 acetone:dichloromethane to afford 60 mg (66%) of4,4-dimethyl-2-oxo-3-pyrrolidinyl(3S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate.ES-LCMS m/z 420 (M+H).

Example 6b Preparation and Separation of(3S)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand (3R)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

(3S)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand (3R)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatewere prepared from4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatefollowing the procedure outlined in example 3d. The diastereomers wereseparated by silica gel chromatography eluting with a gradient of 15-25%acetone in dichloromethane. The configuration of the chiral center atthe 3 position of the 2-pyrrolidinone ring of the diastereomers was notdetermined. The diastereomers are labeled diastereomer one and two,based on the order of elution on silica gel. Diastereomer one:R_(f)=0.51 for silica gel TLC eluting with 25% acetone indichloromethane; ¹H NMR (300 MHz, 80° C., DMSO-d₆) δ 8.88 (d, J=7 Hz,1H), 7.70 (m, 1H), 7.45 (m, 1H), 7.22-7.39 (m, 5H), 5.01 (qnt, J=7 Hz,1H), 4.87 (s, 1H), 4.79 (m, 1H), 3.01 (dd, J=10 Hz, J=32 Hz, 2H), 1.70(m, 1H), 1.56 (m, 1H), 1.48 (d, J=7 Hz, 3H), 1.33 (m, 4H), 1.12 (s, 3H),1.02 (s, 3H), 0.86 (t, J=7 Hz, 3H). ES-LCMS m/z 418 (M+H) HRMSC₂₂H₃₁N₃O₅ m/z 440.2161 (M+Na)⁺ _(Cal.) 440.2180 (M+Na)⁺ _(Obs).Diastereomer two: R_(f)=0.49 for silica gel TLC eluting with 25% acetonein dichloromethane. ¹H NMR (300 MHz, 80° C., DMSO-d₆) δ 8.93 (m, 1H),7.71 (m, 1H), 7.58 (m, 1H), 7.22-7.39 (m, 5H), 5.01 (qnt, J=7 Hz, 1H),4.87 (m, 2H), 3.00 (dd, J=10 Hz, J=33 Hz, 2H), 1.69 (m, 1H), 1.56 (m,1H), 1.47 (d, J=7 Hz, 3H), 1.31 (m, 4H), 1.12 (s, 3H), 0.99 (s, 3H),0.85 (t, J=7 Hz, 3H). ES-LCMS m/z 418 (M+H) HRMS C₂₂H₃₁N₃O₅ m/z 472.2424(M+Na+MeOH)⁺ _(Cal.) 472.2430 (M+Na⁺ MeOH)⁺ _(Obs).

Example 7 1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 7a Preparation of 3-hydroxy-1,4,4-trimethyl-2-pyrrolidinone

To a 0° C. solution of 700 mg (2.9 mmol) of3-{[tert-butyl(dimethyl)silyl]oxy}-1,4,4-trimethyl-2-pyrrolidinone in 10mL of tetrahydrofuran was added 130 mg (3.2 mmol) of sodium hydride (60%in mineral oil), and the reaction mixture was stirred for 10 min before0.27 mL (4.4 mmol) of methyl iodide was added dropwise. The reactionmixture was stirred for 30 min and let warm to room temperature. After 4h, the reaction mixture was diluted with ethyl acetate and then water.The mixture was extracted with ethyl acetate, washed with brine, driedover magnesium sulfate, and concentrated under reduced pressure toafford 550 mg of a dark oil. The oil was dissolved in 15 mL oftetrahydrofuran and cooled to 0° C. A solution of tetrabutylammoniumfluoride in tetrahydrofuran (4.3 mL, 1M, 4.3 mmol) was added, and thereaction mixture was stirred for 30 min. It was then concentrated underreduced pressure, and the residue was purified by silica gelchromatography eluting with 1:9 methanol:ethyl acetate to afford 250 mg(82%) of 3-hydroxy-1,4,4-trimethyl-2-pyrrolidinone. ¹H NMR (300 MHz,DMSO-d₆) δ 5.44 (m, 1H), 3.71 (s, 1H), 3.03 (d, J=9 Hz, 1H), 2.94 (d,J=9 Hz, 1H), 2.72 (s, 3H), 1.08 (s, 3H), 0.89 (s, 3H). ES-LCMS m/z 144(M+H).

Example 7b Preparation of1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatewas prepared from 3-hydroxy-1,4,4-trimethyl-2-pyrrolidinone and(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide following theprocedure outlined in example 3c (57% yield). ¹H NMR (300 MHz, CDCl₃) δ7.25-7.41 (m, 6H), 5.52 (m, 1H), 5.17 (m, 1H), 5.05 (m, 1H), 4.91 and4.21 (m, 1H), 4.21 (m, 1H), 3.90 (m, 1H), 3.18 (m, 1H), 3.04 (m, 1H),2.89 (s, 3H), 1.77 (s, 2H), 1.52 (m, 3H), 1.35 (m, 3H), 1.24 (m, 3H),1.05 (m, 3H), 0.91 (m, 3H). ES-LCMS m/z 434 (M+H).

Example 7c Preparation of1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared from1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatefollowing the procedure outlined in example 3d (77% yield). ¹H NMR (300MHz, DMSO-d₆) δ 9.23 (m, 1H), 7.25 and 7.35 (m, 1H), 7.20-7.38 (m, 5H),4.89-5.05 (m, 2H), 4.80 (m, 1H), 3.15 (m, 1H), 3.02 (d, J=9 Hz, 1H),2.76 (s, 3H), 1.76 (m, 1H), 1.64 (m, 1H), 1.21-1.55 (m, 7H), 0.80-1.12(m, 9H). ES-LCMS m/z 432 (M+H) HRMS C₂₃H₃₃N₃O₅ m/z 454.2318 (M+Na)⁺_(Cal.) 454.2311 (M+Na)⁺ _(Obs).

Example 8 (3S)-1-Benzyl-4,4-dimethylpyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 88a Preparation of (2S)-313-dimethyl-1,2,4-butanetriol

To a 0° C. solution of 5.01 g (38.5 mmol) of (S)-(+)-pantolactone in 150mL of methanol was carefully added 3.72 g (98.5 mmol) of sodiumborohydride. After gas evolution had subsided, the ice-bath was removedand the reaction closely monitored, cooling to 0° C. with an ice-waterbath as needed when gas evolution became vigorous. The ice-water bathwas removed and the reaction mixture was stirred at room temperature for4 h. Dowex 50W×4-400 (H⁺) resin was added to the solution until a pH of7 was achieved, as indicated by wet pH paper. The resin was filteredoff, and the filtrate was evaporated under reduced pressure. Portions ofmethanol and toluene were distilled from the resulting oil, which wasfurther dried under high vacuum to afford 5.16 g (quantitative yield) of(2S)-3,3-dimethyl-1,2,4-butanetriol. ¹H NMR (300 MHz, CDCl₃) δ 3.49-3.82(m, 5H), 3.11 (d, J=4 Hz, 1H), 2.62 (m, 1H), 2.42 (m, 1H), 0.98 (d, J=6Hz, 6H).

Example 8b Preparation of (2S)-2-hydroxy-3,3-dimethyl-4[(methylsulfonyl)oxy]butyl methanesulfonate

To a 0° C. solution of 25.3 g (189 mmol) of(2S)-3,3-dimethyl-1,2,4butanetriol in 170 mL of pyridine was addeddropwise 29.1 mL (378 mmol) of methanesulfonyl chloride. The reactionmixture was allowed to slowly warm to room temperature, stirred for 18h, and then diluted with dichloromethane. To the mixture was added 200mL of 1 N hydrochloric acid followed by concentrated hydrochloric aciduntil the pH of the aqueous phase was brought to a value of 2. Themixture was extracted with dichloromethane, and the combined extractswere washed with brine and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 10%acetone in dichloromethane to afford 21.75 g (52.10%) of(2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butylmethanesulfonate. ¹H NMR (300 MHz, DMSO-d₆) δ 5.48 (d, J=6 Hz, 1H), 4.30(dd, J=2 Hz, J=10 Hz, 1H), 3.91-4.05 (m, 3H), 3.16 (d, J=4 Hz, 6H), 0.90(d, J=13 Hz, 6H).

Example 8c Preparation of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol

A solution of 21.7 g (75 mmol) of (2S)-2-hydroxy-3,3-dimethyl-4[(methylsulfonyl)oxy]butyl methanesulfonate and 24.4 mL (228 mmol) ofbenzylamine in 200 mL of ethanol was heated at 120° C. for 18 h in a 400mL capacity bomb. The reaction mixture was allowed to cool to roomtemperature, the bomb was vented, and the reaction mixture wasconcentrated under reduced pressure to 100 mL The reaction was dilutedwith 50 mL of water and made acidic with concentrated hydrochloric acid.The aqueous phase was then washed with ether, made basic with 5M aqueoussodium hydroxide, and extracted with ether. The ether extract wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography eluting with 0.25:9.75 2M ammonia inmethanol:ethyl acetate to afford 13.8 g (90%) of(3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol. ¹H NMR (300 MHz, CDCl₃) δ7.30-7.36 (m, 5H), 3.77 (br s, 1H), 3.65 (s, 2H), 2.93-2.99 (m, 1H),2.55-2.64 (m, 2H), 2.31 (d, J=9 Hz, 1H), 1.76 (d₁J=7 Hz, 1H), 1.09 (d,J=1 Hz, 6H).

Example 8d Preparation of(3S)-1-benzyl-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

To a −20° C. solution of 110 mg (0.54 mmol) of(3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol in 3 mL of dichloromethane wasadded 0.58 mL (1.1 mmol) of 1.93 M phosgene in toluene. The mixture wasstirred for 3 min before 0.05 mL (0.59 mmol) of pyridine was addeddropwise. The reaction mixture was allowed to warm to room temperatureand was stirred overnight. A stream of nitrogen was then blown throughthe solution for 15 min and the residue was dissolved in 1 mL oftetrahydrofuran. To this solution was added a solution of 140 mg (0.54mmol) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide and0.15 mL (1.1 mmol) of triethylamine in tetrahydrofuran. The reactionmixture was stirred at room temperature overnight. It was thenconcentrated under reduced pressure and the residue was purified bysilica gel chromatography eluting with 25% acetone in hexanes to afford110 mg (41%) of(3S)-1-benzyl-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate.¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=8 Hz, 1H), 7.40-7.19 (m, 10H),6.47 (d, J=9 Hz, 1H), 5.58 (d, J=7 Hz, 1H), 4.92 (qnt, J=7 Hz, 1H), 4.55(dd, J=7 Hz, J=4 Hz, 1H), 4.37 (d, J=4 Hz, 1H), 3.92-3.72 (m, 3H), 3.57(m, 2H), 3.01 (dd, J=10 Hz, J=7 Hz, 1H), 2.41 (m, 1H), 1.58-0.81 (m,18H). ES-LCMS m/z 496 (M+H).

Example 8e Preparation of (3S)-1-benzyl-4,4-dimethylpyrrolidinyl 1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

To a solution of 0.029 mL (0.33 mmol) of oxalyl chloride in 2 mL ofdichloromethane at −60° C. was added 0.047 mL (0.67 mmol) ofdimethylsulfoxide dropwise. After 3 min, a solution of 75 mg (0.15 mmol)of(3S)-1-benzyl-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatein 2 mL of dichloromethane was added, and the mixture was stirred for 10min before 0.11 mL (0.76 mmol) of triethylamine was added. The reactionmixture was then allowed to warm to room temperature and was stirred for15 min before being subjected directly to column chromatography onsilica gel. Elution with 10% acetone in dichloromethane afforded 50 mg(66%) of (3S)-1-benzyl-4,4-dimethylpyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. ¹H NMR (300MHz, Temp=80° C., DMSO-d₆) δ 8.90 (m, 1H), 7.20-7.39 (m, 10H), 5.00 (m,1H), 4.80 (m, 1H), 4.55 (m, 1H), 3.60 (s, 2H), 3.25-3.00 under waterpeak (m, 4H), 2.42 (m, 1H), 1.85-0.65 (m, 18). ES-LCMS m/z 494 (M+H);HRMS C₂₉H₃₉N₃O₄ m/z 494.3019 (M+Na)⁺ _(Cal) 494.3032 (M+Na)⁺ _(Obs).

Example 9 (3S)-1-Benzoyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 9a Preparation of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

A solution of 8.0 g (16 mmol) of (3S)-1-benzyl-4,4-dimethylpyrrolidinyl(1s)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatein 100 mL of ethanol was stirred under hydrogen (50 psi) in the presenceof 0.70 g of 10% Pd/C. After 72 h, 100 mg of fresh catalyst was added,and the mixture was stirred under hydrogen (50 psi) for an additional 4h. At that time, 800 mg of fresh catalyst was added, and the mixture wasstirred for an additional 18 h under hydrogen (50 psi). The catalyst wasfiltered off over celite and the filtrate was concentrated. The residuewas purified by silica gel chromatography eluting with 1:5 2M ammonia inmethanol: dichloromethane to afford 4.87 g (75%) of(3S)-4,4-dimethylpyrrolidinyl(3S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateas a pale yellow glass. ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=8 Hz,1H); 7.19-7.40 (m, 5H); 6.56 (d, J=9 Hz) and 6.39 (d, J=9 Hz) total 1H,5.73 (m, 1H); 4.95 (qnt, J=8 Hz, 1H); 4.51 (m, 1H); 3.89 (m) and 3.96(m) total 1H); 3.76 (m, 1H); 3.27 (m, 4H); 2.61 (dd, J=12 Hz, J=3 Hz,1H); 1.60-0.71 (m, 18H). ES-LCMS m/z 406 (M+H).

Example 9b Preparation of(3S)-1-benzoyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Benzoyl chloride (0.032 mL, 0.28 mmol) was added to a solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(101 mg, 0.25 mmol) in dichloromethane (4 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (280 mg, 1.8 mmol/g, 0.50mmol). The resulting mixture was shaken at 800 Hz for 1.5 h.Tris-(2-aminoethyl)amine polystyrene (103 mg, 2.43 mmol/g, 0.25 mmol)was then added, and the mixture was shaken for an additional 4 h. Solidswere then removed by filtration, rinsing with five 2 mL portions ofdichloromethane. The filtrate and rinses were combined and concentratedto afford a white film (138 mg, quantitative yield). The film wasdissolved in dichloromethane (2.5 mL), and Dess-Martin periodinane (118mg, 0.310 mmol) was added. The resulting mixture was stirred for 3 h,and then the reaction mixture was subjected directly to columnchromatography on silica gel. Elution with 50% acetone indichloromethane afforded(3S)-1-benzoyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamateas a gum (112 mg, 79%), after drying under vacuum. ¹H NMR (300 MHz,DMSO-d₆) δ 9.26 (d, J=8 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 7.40-7.33 (m,4H), 7.31-7.23 (m, 1H), 5.92-5.84 (m, 1H), 5.71-5.63 (m, 1H), 5.40 (s,1H), 5.08-4.96 (m, 1H), 4.85-4.78 (m, 1H), 4.16 (1/2 Abq, J=8 Hz, 1H),4.06 (1/2Abq, J=8 Hz, 1H), 3.04-2.91 (m, 2H), 2.55 (part of doverlapping DMSO, 3H), 1.74-1.61 (m, 1H), 1.46 (d, J=7 Hz, 1H),1.45-1.29 (m, 5H), 1.12 (s, 1H), 1.05 (s, 1H). ES-LCMS m/z 493 (M+H)HRMS C₂₄H₃₄N₄O₇ m/z 491.2505 (M+H)_(Cal.) 491.2490 (M+H)_(Obs).

Example 10(3S)-1-Acetyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Acetyl chloride (0.0094 mL, 0.13 mmol) was added to a solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (133 mg, 1.8 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 1 h. Additionalacetylchloride (0.004 mL, 0.08 mmol) was added, and the mixture wasshaken for 1 h. Tris-(2-aminoethyl)amine polystyrene (52 mg, 2.43mmol/g, 0.12 mmol) was then added, and the mixture was shaken for anadditional 5 h. Solids were then removed by filtration, rinsing withfour 1 mL portions of dichloromethane. The filtrate and rinses werecombined and concentrated to a volume of 4 mL. Sodium bicarbonate (15mg, 0.18 mmol) and Dess-Martin periodinane (66 mg, 0.18 mmol) wereadded. The resulting mixture was shaken at 800 Hz for 30 min. More DessMartin periodinane (30 mg, 0.08 mmol) was added, and the reactionmixture was shaken for 15 min. It was then subjected directly to columnchromatography on silica gel. Elution with a gradient of 5-20% acetonein dichloromethane afforded impure product, which was purified furtherby column chromatography on silica gel. Elution with 100/a acetone indichloromethane afforded(3S)-1-acetyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamateas a solid white foam (26 mg, 46%) that contained dichloromethane andacetone (0.16 eq. and 0.11 eq. respectively, based on integration ofsignals in the ¹H NMR spectrum), after drying under vacuum. ¹H NMR (300MHz, DMSO-d₆, Temp=100° C.) δ 8.82-8.72 (m, 1H); 7.40-7.20 (m, 6H);5.06-4.96 (m, 1H); 4.86-4.78 (m, 1H); 4.78-4.66 (m, 1H); 3.88-3.82 (m,1H); 3.76-3.63 (m, 1H); 3.40-3.25 (m, 1H); 1.95 (s) and 1.94 (s) total3H, 1.78-1.64 (m, 1H); 1.62-1.51 (m, 1H); 1.49 (d, J=7 Hz, 1H);1.40-1.20 (m, 4H); 1.05 (br s, 6H); 0.85 (m, 3H). ES-LCMS m/z 446 (M+H)HRMS C₂₄H₃₅N₃O₅ m/z 446.2644 (M+H)_(Cal.) 446.2632 (M+H)_(Obs).

Example 11(3S)-4,4-Dimethyl-1-(phenylacetyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Phenylacetyl chloride (0.0178 mL, 0.132 mmol) was added to a solution of(3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (133 mg, 1.8 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 1 h.Tris-(2-aminoethyl)amine polystyrene (52 mg, 2.43 mmol/g, 0.12 mmol) wasthen added, and the mixture was shaken for an additional 6 h. Solidswere then removed by filtration, rinsing with four 1 mL portions ofdichloromethane. The filtrate and rinses were combined and concentratedto a volume of 4 mL Sodium bicarbonate (15 mg, 0.18 mmol) andDess-Martin periodinane (66 mg, 0.18 mmol) were added. The resultingmixture was shaken at 800 Hz for 30 min. It was then subjected directlyto column chromatography on silica gel. Elution with 10% acetone indichloromethane afforded impure product, which was further purified bycolumn chromatography on silica gel under the same conditions. In thismanner,(3S)-4,4-dimethyl-1-(phenylacetyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamateas a solid white foam (23 mg, 37%), after drying under vacuum. ¹H NMR(300 MHz, DMSO-d₆, Temp=100° C.) δ 8.78 (m, 1H), 7.40-7.20 (m, 11H),5.06-4.98 (m, 1H), 4.86-4.78 (m, 1H), 4.84-4.68 (m, 2H), 4.00-3.86 (m,1H), 3.80-3.65 (m, 1H), 3.63 (br s, 2H), 3.50-3.20 (m, 2H), 1.74-1.64(m, 1H), 1.60-1.50 (m, 1H), 1.48 (d, J=7 Hz, 1H), 1.38-1.22 (m, 4H),1.03 (s, 3H), 1.01 (s, 3H), 0.87 (m, 3H). ES-LCMS m/z 522 (M+H) HRMSC₃₀H₃₉N₃O₅ m/z 522.2968 (M+H)_(Cal.) 522.2971 (M+H)_(Obs).

Example 12(3S)-1-(5-Isoxazolylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 5-isoxazolecarbonyl chloride in dichloromethane (0.264 mL,0.500 M, 0.132 mmol) was added to a solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of 5-isoxazolecarbonyl chloride in dichloromethane (0.132 mL,0.500 M, 0.064 mmol) was added, and the mixture was shaken for another 2h. Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g, 0.12 mmol)was then added, and the mixture was shaken for an additional 18 h.Solids were then removed by filtration, rinsing with five 1 mL portionsof dichloromethane. The filtrate and rinses were combined andconcentrated. The residue was then redissolved in dichloromethane (2mL). Sodium bicarbonate (13 mg, 0.16 mmol) and a solution of Dess-Martinperiodinane in dichloromethane (0.75 mL, 0.20 M, 0.15 mmol) were added,and the resulting mixture was shaken at 800 Hz for 1 h. It was thensubjected directly to column chromatography on silica gel. Elution witha gradient of 5-10% acetone in dichloromethane afforded impure product,which was further purified by column chromatography on silica gel.Elution with 5% acetone in dichloromethane afforded(3S)-1-(5-isoxazolylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamateas a solid white foam (33 mg, 55%) after drying under vacuum. ¹H NMR(300 MHz, DMSO-d₆) δ 9.16 (m) and 9.01 (m) total 1H; 8.77 (d, J=2 Hz)and 8.76 (d, J=2 Hz) total 1H, 7.68 (m, 1H); 7.35-7.17 (m, 5H);7.07-7.00 (m, 1H); 5.01-4.63 (m, 3H); 4.25-4.19 (m) and 3.95-3.89 (m)total 1H, 3.70-3.43 (m, 3H); 1.67-1.53 (m, 1H); 1.48-1.35 (m, 4H);1.31-1.11 (m, 4H); 1.05 (s), 1.04 (s), and 1.01 (s) total 6H, 0.82-0.73(m, 3H). ES-LCMS m/z 499 (M+H) HRMS C₂₆H₃₄N₄O₆ m/Z 499.2557 (M+H)cal.499.2530 (M+H)_(Obs).

Example 13(3S)-4,4-Dimethyl-1-[(4-methyl-1,2,3-thiadiazol-5-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride indichloromethane (0.264 mL, 0.500 M, 0.132 mmol) was added to a solutionof(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz. A second portion of4-methyl-1,2,3-thiadiazole-5-carbonyl chloride in dichloromethane (0.132mL, 0.500 M, 0.064 mmol) was added after 2h, and a third (0.264 mL,0.500 M. 0.132 mmol) after 4h. The mixture was shaken for another 18 h.Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g, 0.12 mmol) wasthen added, and the mixture was shaken for an additional 6 h. Solidswere then removed by filtration, rinsing with five 1 mL portions ofdichloromethane. The filtrate and rinses were combined and concentrated.The residue was then redissolved in dichloromethane (2 mL). Sodiumbicarbonate (13 mg, 0.16 mmol) and a solution of Dess-Martin periodinanein dichloromethane (0.75 mL, 0.20 M. 0.15 mmol) were added, and theresulting mixture was shaken at 800 Hz for 1 h. It was then subjecteddirectly to column chromatography on silica gel. Elution with a gradientof 5-100% acetone in dichloromethane afforded impure product, which wasfurther purified by column chromatography on silica gel. Elution with 5%acetone in dichloromethane afforded the title compound as a gum, fromwhich three 2 mL portions of ether were distilled. In this manner,(3S)-4,4-dimethyl-1-[(4-methyl-1,2,3-thiadiazol-5-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a colorless-gum (32 mg, 48%) that contained ether (0.4eq. based on integration of signals in the ¹H NMR spectrum), afterdrying under vacuum. ¹H NMR (300 MHz, DMSO-d₆) δ 9.29-9.07 (m, 1H);7.71-7.67 (m, 1H), 7.34-7.18 (m, 5H); 5.01-4.57 (m, 3H); 3.98-3.69 (m,1H); 3.46 (m, 1H); 3.18-3.05 (m, 2H); 2.67 (s) and 2.65 (s) total 3H,1.67-1.55 (m, 1H); 1.44-1.34 (m, 4H); 1.32-1.12 (m, 4H); 1.08-0.91 (m,6H); 0.85-0.73 (m, 3H). ES-LCMS m/z 530 (M+H) HRMS C₂₆H₃₅N₅O₅S m/z530.2437 (M+H)_(Cal.) 530.2462 (M+H)_(Obs).

Example 14(3S)-1-[(3-tert-Butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-4,4-dimethylpyrrolidinyl(3S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 3-tert-butyl-1-methyl-1H-pyrazole-5-carbonyl chloride indichloromethane (0.264 mL, 0.500 M, 0.132 mmol) was added to a solutionof(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of 3-tert-butyl-1-methyl-1H-pyrazole-5-carbonyl chloride indichloromethane (0.132 mL, 0.500 M, 0.064 mmol) was then added, and themixture was shaken for another 2 h. Tris-(2-aminoethyl)amine polystyrene(29 mg, 4.08 mmol/g, 0.12 mmol) was then added, and the mixture wasshaken for an additional 18 h. Solids were then removed by filtration,rinsing with five 1 mL portions of dichloromethane. The filtrate andrinses were combined and concentrated. The residue was then redissolvedin dichloromethane (2 mL). Sodium bicarbonate (13 mg, 0.16 mmol) and asolution of Dess-Martin periodinane in dichloromethane (0.75 mL, 0.20 M,0.15 mmol) were added, and the resulting mixture was shaken at 800 Hzfor 1 h. A second portion of Dess-Martin periodinane (21 mg, 0.06 mmol)was added, and the mixture was shaken for 15 min. It was then subjecteddirectly to column chromatography on silica gel. Elution with a gradientof 5-10% acetone in dichloromethane afforded impure product, which wasfurther purified by column chromatography on silica gel. Elution with 5%acetone in dichloromethane afforded the title compound as a solid, fromwhich three 2 mL portions of ether were distilled. In this manner,(3S)-1-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a white solid (36 mg, 53%), after drying under vacuum.¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 8.80-8.73 (m, 1H), 7.38-7.21(m, 6H), 6.44 (br s, 1H), 5.05-4.95 (m, 1H), 4.87-4.73 (m, 2H),4.05-3.94 (m, 1H), 3.88 (s, 3H), 3.49-3.39 (m, 3H), 1.75-1.63 (m, 1H),1.56-1.45 (m, 1H), 1.47 (d, J=7 Hz, 3H), 1.30 (s, 9H), 1.36-1.24 (m,4H), 1.08 (br s, 6H), 0.84 (t, J=7 Hz, 3H). ES-LCMS m/z 568 (M+H) HRMSC₃₁H₄₅N₅O₅ m/z 568.3499 (M+H)_(Cal.) 568.3503(M+H)_(Obs).

Example 15(3S)-4,4-Dimethyl-1-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]pyrrolidinyl(1s)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride indichloromethane (0.264 mL, 0.500 M, 0.132 mmol) was added to a solutionof(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride indichloromethane (0.264 mL, 0.500 M, 0.132 mmol) was then added, and themixture was shaken for another 2 h. A third portion of5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride indichloromethane (0.132 mL, 0.500 M, 0.064 mmol) was then added, and themixture was shaken for 18 h. Tris-(2-aminoethyl)amine polystyrene (29mg, 4.08 mmol/g, 0.12 mmol) was added, and the mixture was shaken for anadditional 6 h. Solids were then removed by filtration, rinsing withfive 1 mL portions of dichloromethane. The filtrate and rinses werecombined and concentrated. The residue was then redissolved indichloromethane (2 mL). Sodium bicarbonate (13 mg, 0.16 mmol) and asolution of Dess-Martin periodinane in dichloromethane (0.75 mL, 0.20 M,0.15 mmol) were added, and the resulting mixture was shaken at 800 Hzfor 1 h. It was then subjected directly to column chromatography onsilica gel. Elution with a gradient of 5-10% acetone in dichloromethaneafforded impure product, which was further purified by columnchromatography on silica gel. Elution with 5% acetone in dichloromethaneafforded the title compound as a gum, from which three 2 mL portions ofether were distilled. In this manner,(3S)-4,4-dimethyl-1-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a colorless gum (25 mg, 33%) that contained ether (0.65eq. based on integration of signals in the ¹H NMR spectrum), afterdrying under vacuum. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18-9.14 (m); 9.10 (d,J=8 Hz) and 8.94 (d, J=9 Hz) total 1H, 8.00 (d, J=8 Hz, 2H); 7.69-7.66(m, 1H); 7.61-7.54 (m, 2H); 7.48-7.41 (m, 1H); 7.35-7.06 (m, 5H);5.01-4.64 (m, 3H); 4.36-4.28 (m) and 3.97-3.92 (m) total 1H, 3.93-3.89(m, 1H); 3.80-3.64 (m, 1H); 3.60-3.43 (m, 1H); 1.66-1.52 (m, 1H);1.46-1.35 (m, 1H); 1.31-1.12 (m, 4H); 1.10 (s), 1.07 (s), 1.05 (s), and1.02 (s) total 6H; 0.89-0.68 (m, 3H). ES-LCMS-m/z 589 (M+H) HRMSC₃₂H₄₀N₆O₅ m/z 589.3138 (M+H)_(Cal.) 589.3137(M+H)_(Obs).

Example 16(3S)-1-(1,3-Benzodioxol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 1,3-benzodioxole-5-carbonyl chloride in 1:1acetonitrile:dichloromethane (0.528 mL, 0.250 M, 0.132 mmol) was addedto a solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of 3-benzodioxole-5-carbonyl chloride in 1:1acetonitrile:dichloromethane (0.264 mL, 0.250 M, 0.064 mmol) was added,and the mixture was shaken for another 2 h. Tris-(2-aminoethyl)aminepolystyrene (29 mg, 4.08 mmol/g, 0.12 mmol) was then added, and themixture was shaken for an additional 18 h. Solids were then removed byfiltration, rinsing with five 1 mL portions of dichloromethane. Thefiltrate and rinses were combined and concentrated. The residue was thenredissolved in dichloromethane (2 mL). Sodium bicarbonate (13 mg, 0.16mmol) and a solution of Dess-Martin periodinane in dichloromethane (1.00mL, 0.15 M, 0.15 mmol) were added, and the resulting mixture was shakenat 800 Hz for 1 h. A second portion of Dess-Martin periodinane (15 mg,0.04 mmol) was added, and the mixture was shaken for 15 min. Sodiumbicarbonate (15 mg, 0.18 mmol) was then added, the mixture was filtered,and the filtrate was subjected directly to column chromatography onsilica gel. Elution with a gradient of 5-10% acetone in dichloromethaneafforded impure product, which was further purified by columnchromatography on silica gel. Elution with 5% acetone in dichloromethaneafforded(3S)-1-(1,3-benzodioxol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamateas a solid white foam (42 mg, 63%), after drying under vacuum. ¹H NMR(300 MHz, DMSO-d₆, Temp=100° C.) δ 8.82-8.74 (m, 1H), 7.38-7.22 (m, 6H),7.07 (m, 1H), 7.05 (br s, 1H), 6.95 (m, 1H), 6.08 (s, 2H), 5.05-4.95 (m,1H), 4.86-4.76 (m, 1H), 4.71 (br s, 1H), 3.94 (dd, J=13 Hz, 5 Hz, 1H),3.41-3.29 (m, 3H), 1.77-1.62 (m, 1H), 1.60-1.45 (m, 1H), 1.47 (d, J=7Hz, 3H), 1.38-1.20 (m, 4H), 1.05 (br s, 6H), 0.84 (t, J=7 Hz, 3H).ES-LCMS m/z 552 (M+H) HRMS C₃₀H₃₇N₃O₇ m/z 552.2710 (M+H)_(Cal.) 552.2714(M+H)_(Obs).

Example 17(3S)-1-(1-Benzothien-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 1-benzothiophene-2-carbonyl chloride in 1:1acetonitrile:dichloromethane (0.528 mL, 0.250 M, 0.132 mmol) was addedto a solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of 1-benzothiophene-2-carbonyl chloride in 1:1acetonitrile:dichloromethane (0.264 mL, 0.250 M, 0.064 mmol) was thenadded, and the mixture was shaken for another 2 h.Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g, 0.12 mmol) wasthen added, and the mixture was shaken for an additional 18 h. Solidswere then removed by filtration, rinsing with five 1 mL portions ofdichloromethane. The filtrate and rinses were combined and concentrated.The residue was then redissolved in dichloromethane (2 mL). Sodiumbicarbonate (13 mg, 0.16 mmol) and a solution of Dess-Martin periodinanein dichloromethane (1.00 mL, 0.15 M, 0.15 mmol) were added, and theresulting mixture was shaken at 800 Hz for 1 h. A second portion ofDess-Martin periodinane (15 mg, 0.04 mmol) was added, and the mixturewas shaken for 15 min. Sodium bicarbonate (15 mg, 0.18 mmol) was thenadded, the mixture was filtered, and the filtrate was subjected directlyto column chromatography on silica gel. Elution with a gradient of 5-10%acetone in dichloromethane afforded impure product, which was furtherpurified by column chromatography on silica gel. Elution with 5% acetonein dichloromethane afforded the title compound as a solid, from whichthree 2 mL portions of ether were distilled. In this manner,(3S)-1-(1-benzothien-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a white solid (45 mg, 64%) that contained ether (0.36eq. based on integration of signals in the ¹H NMR spectrum), afterdrying under vacuum. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18-9.13 (m, 1H);8.04-7.88 (m, 3H); 7.70 (d, J=8 Hz, 1H); 7.49-7.38 (m, 2H); 7.37-7.11(m, 5H); 5.01-4.87 (m, 1H); 4.85-4.66 (m, 2H); 4.36 (dd, J=12 Hz, 6 Hz)and 3.96 (dd, J=13 Hz, 5 Hz) total 1H, 3.86-3.62 (m, 2H); 3.53-3.38 (m,1H); 1.67-1.51 (m, 1H); 1.48-1.34 (m, 4H); 1.32-1.13 (m, 4H); 1.10 (s),1.09 (s), 1.07 (s), 1.05 (s), 1.02 (5), and 1.00 (s) total 6H; 0.86-0.68(m, 3H). ES-LCMS m/z 564 (M+H) HRMS C₃₁H₃₇N₃O₅ m/z 564.2532 (M+H)_(Cal.)564.2522 (M+H)_(Obs).

Example 18 (3S)-4,4-Dimethyl-1-(2-naphthoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 2-naphthoyl chloride in 1:1 acetonitrile:dichloromethane(0.528 mL, 0.250 M, 0.132 mmol) was added to a solution of(3S)-4,4-dimethylpyrrolidinyl(3S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of 2-naphthoyl chloride in 1:1 acetonitrile:dichloromethane(0.264 mL, 0.250 M, 0.064 mmol) was then added, and the mixture wasshaken for another 2 h. A third portion of 2-naphthoyl chloride (0.528mL, 0.250 M, 0.132 mmol) was added, and the mixture was shaken for 18 h.Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g, 0.12 mmol) wasthen added, and the mixture was shaken for an additional 6 h. Solidswere then removed by filtration, rinsing with five 1 mL portions ofdichloromethane. The filtrate and rinses were combined and concentrated.The residue was then redissolved in dichloromethane (2 mL). Sodiumbicarbonate (13 mg, 0.16 mmol) and a solution of Dess-Martin periodinanein dichloromethane (1.00 mL 0.15 M. 0.15 mmol) were added, and theresulting mixture was shaken at 800 Hz for 1 h. A second portion ofDess-Martin periodinane (15 mg, 0.04 mmol) was added, and the mixturewas shaken for 15 min. Sodium bicarbonate (15 mg, 0.18 mmol) was thenadded, the mixture was filtered, and the filtrate was subjected directlyto column chromatography on silica gel. Elution with a gradient of 5-10%acetone in dichloromethane afforded impure product, which was furtherpurified by column chromatography on silica gel. Elution with 5% acetonein dichloromethane afforded the title compound as a gum, from whichthree 2 mL portions of ether were distilled. In this manner,(3S)-4,4-dimethyl-1-(2-naphthoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a white solid (45 mg, 62%) that contained ether (0.6 eq.based on integration of signals in the ¹H NMR spectrum), after dryingunder vacuum. ¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (d, J=8 Hz, 1H); 9.17 (d,J=8 Hz), 9.10 (d, J=8 Hz) and 9.02 (d, J=9 Hz) total 1H, 8.15-7.92 (m,414); 7.72-7.54 (m, 4H); 7.44-7.15 (m, 5H); 5.02-4.51 (m, 3H); 4.123.89(m, 1H); 3.48-3.35 (m, 3H); 1.70-1.04 (m, 12H); 0.95 (s), 0.93 (s), and0.91 (s) total 3H, 0.82-0.67 (m, 3H). ES-LCMS m/z 558 (M+H) HRMSC₃₃H₃₉N₃O₅ m/z 558.2968 (M+H)_(Cal.) 558.2967 (M+H)_(Obs).

Example 19(3S)-4,4-Dimethyl-1-[(5-methyl-3-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of presumed 5-methyl-3-isoxazolecarbonyl chloride in 1:1acetonitrile:dichloromethane (0.528 mL 0.250 M, 0.132 mmol) was added toa solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of presumed 5-methyl-3-isoxazolecarbonyl chloride in 1:1acetonitrile:dichloromethane (0.264 mL, 0.250 M, 0.064 mmol) was addedthen, and the mixture was shaken for another 18 h.Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g, 0.12 mmol) wasthen added, and the mixture was shaken for an additional 6 h. Solidswere removed by filtration, rinsing with five 1 mL portions ofdichloromethane. The filtrate and rinses were combined and concentrated.Analysis of the filtrate by LC-MS showed the presence of unreacted(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 5-methyl-3-isoxazolecarboxylic acid. The residue was thenredissolved in dichloromethane (2 mL).N-Cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (350 mg, 1-1.5mmol/g, 0.35-0.52 mmol) was added, followed by a solution of1-hydroxybenzotriazole in 20% N,N-dimethylformamide in dichloromethane(1.2 mL, 120 mM, 0.14 mmol). The resulting mixture was shaken for 4.5 hat 800 Hz. Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g,0.12 mmol) was then added, and the mixture was shaken for an additional18 h. Solids were removed by filtration, rinsing with five 1 mL portionsof dichloromethane. The filtrate and rinses were combined andconcentrated to a volume of 2 mL Sodium bicarbonate (13 mg, 0.16 mmol)and Dess-Martin periodinane (55 mg, 0.15 mmol) were added, and theresulting mixture was shaken at 800 Hz for 1 h. The mixture was washedwith saturated aqueous sodium thiosulfate (2 mL), and the aqueous washwas back-extracted twice with 1 mL portions of dichloromethane. Thedichloromethane layers were combined, and subjected to columnchromatography on silica gel. Elution with 5% acetone in dichloromethaneafforded impure product, which was further purified by columnchromatography on silica gel. Elution with 40% ethyl acetate in hexaneafforded the title compound as a gum, from which three 2 mL portions ofether were distilled. In this manner,(3S)-4,4-dimethyl-1-[(5-methyl-3-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a colorless gum (35 mg, 54%) that contained ether (0.32eq. based on integration of signals in the ¹H NMR spectrum), afterdrying under vacuum. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 8.76 (m,1H); 7.38-7.22 (m, 6H); 6.47 (s, 1H); 5.05-4.94 (m, 1H); 4.88-4.74 (m,2H); 4.16-4.07 (m) and 3.98-3.90 (m) total 1H, 3.72-3.38 (m, 3H); 2.48(s, 3H); 1.76-1.63 (m, 1H); 1.60-1.45 (m, 1H); 1.47 (d, J=7 Hz, 3H);1.38-1.22 (m, 4H); 1.10 (s) and 1.09 (s) total 3H, 1.06 (s) and 1.06 (s)total 3H, 0.89-0.80 (m, 3H). ES-LCMS m/513 (M+H) HRMS C₂₇H₃₆N₄O₆ m/z535.2533 (M+Na)_(Cal.) 535.2537 (M+Na)_(Obs).

Example 20(3S)-1-([1,1′-Biphenyl]-4ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of presumed [1,1′-biphenyl]-4-carbonyl chloride in 1:1:0.5acetonitrile:dichloromethane:N,N-dimethylformamide (0.660 mL, 0.200 M,0.132 mmol) was added to a solution of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(49 mg, 0.12 mmol) in dichloromethane (2 mL) in the presence of3-(morpholino)propylpolystyrenesulfonamide (118 mg, 2.03 mmol/g, 0.24mmol). The resulting mixture was shaken at 800 Hz for 2 h. A secondportion of presumed [1,1′-biphenyl]-4-carbonyl chloride in 1:1:0.5acetonitrile:dichloromethane:N,N-dimethyl formamide (0.330 mL, 0.200 M,0.064 mmol) was added, and the mixture was shaken for another 18 h.Tris-(2-aminoethyl)amine polystyrene (29 mg, 4.08 mmol/g, 0.12 mmol) wasthen added, and the mixture was shaken for an additional 6 h. Solidswere then removed by filtration, rinsing with five 1 mL portions ofdichloromethane. The filtrate and rinses were combined and concentrated.Analysis of the filtrate by LC-MS showed the presence of unreacted(3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand [1,1′-biphenyl]-4 carboxylic acid. The residue was then redissolvedin dichloromethane (2 mL). N-Cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (350 mg, 1-1.5 mmol/g, 0.35-0.52 mmol) was added, followedby a solution of 1-hydroxybenzotriazole in 20% N,N-dimethylformamide indichloromethane (1.2 mL 120 mM, 0.14 mmol). The resulting mixture wasshaken for 4.5 h at 800 Hz. Tris-(2-aminoethyl)amine polystyrene (29 mg,4.08 mmol/g, 0.12 mmol) was then added, and the mixture was shaken foran additional 18 h. Solids were removed by filtration, rinsing with five1 mL portions of dichloromethane. The filtrate and rinses were combinedand concentrated to a volume of 2 mL Sodium bicarbonate (13 mg, 0.16mmol) and Dess-Martin periodinane (55 mg, 0.15 mmol) were added, and theresulting mixture was shaken at 800 Hz for 1 h. The mixture was washedwith saturated aqueous sodium thiosulfate (2 mL). The aqueous wash wasback-extracted twice with 1 mL portions of dichloromethane. Thedichloromethane layers were combined, and subjected to columnchromatography on silica gel. Elution with 5% acetone in dichloromethaneafforded impure product, which was further purified by columnchromatography on silica gel. Elution with 40% ethyl acetate in hexaneafforded the title compound as a foam, from which three 2 mL portions ofether were distilled. In this manner,(3S)-1-([1,1′-biphenyl]-4ylcarbonyl)-4,4dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamatewas obtained as a white foam (27 mg, 38%) that contained-ether-(0.17 eq.based on integration of signals in the ¹H NMR spectrum), after dryingunder vacuum. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 8.80-8.72 (m,1H), 7.73 (m, 4H), 7.63 (m, 2H), 7.64-7.49 (m, 2H), 7.45-7.22 (m, 7H),6.47 (s, 1H), 5.05-4.95 (m, 1H), 4.87-4.71 (m, 2H), 3.98 (dd, J=13 Hz, 6Hz, 1H), 3.45-3.36 (m, 3H), 1.76-1.64 (m, 1H), 1.61-1.49 (m, 1H), 1.48(d, J=7 Hz, 3H), 1.38-1.21 (m, 4H), 1.07 (br s, 6H), 0.86-0.82 (m, 3H).ES-LCMS m/z 584 (M+H) HRMS C₃₅H₄₁N₃O₅ m/z 584.3124 (M+H)_(Cal.) 584.3104(M+H)_(Obs).

Example 21(3S)-1-(1H-Indol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

A solution of 1-hydroxybenzotriazole in 20% N,N-dimethylformamide indichloromethane (1.2 mL, 120 mM, 0.14 mmol) was added to a slurry of1H-indole-5-carboxylic acid (21 mg, 0.13 mmol) in dichloromethane (1.0mL) in the presence of N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (350 mg, 1-1.5 mmol/g, 0.35-0.52 mmol). The resultingmixture was shaken at 800 Hz for 20 min. A solution of

-   (3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate    in dichloromethane (1.0 mL, 120 mM, 0.12 mmol) was added, and the    reaction mixture was shaken at 800 Hz for 16 h.    Tris-(2-aminoethyl)amine polystyrene (50 mg, 4.08 mmol/g, 0.20 mmol)    was then added, and the mixture was shaken for an additional 24 h.    Solids were then removed by filtration, rinsing with five 1 mL    portions of dichloromethane. The filtrate and rinses were combined    and concentrated. The residue was then redissolved in    dichloromethane (2 mL). Sodium bicarbonate (13 mg, 0.16 mmol) and a    solution of Dess-Martin periodinane (1.0 mL, 180 mM, 0.18 mmol) were    added, and the resulting mixture was shaken at 800 Hz for 1.5 h.    Saturated aqueous sodium thiosulfate (2 mL) was then added, and the    mixture was shaken at 800 Hz for 30 min. The layers were separated,    and the aqueous-wash was back-extracted with dichloromethane (1 mL).    The dichloromethane layers were combined, and subjected to column    chromatography on silica gel. Elution with a gradient of 5-50%    acetone in dichloromethane afforded impure product, which was    further purified by column chromatography on silica gel. Elution    with 500/a ethyl acetate in hexane afforded    (3S)-1-(1H-indol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate    as a colorless glass (23 mg, 34%) that contained ethyl acetate (0.28    eq. based on integration of signals in the ¹H NMR spectrum), after    drying under vacuum., ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ    11.03 (br s, 1H), 8.72 (m, 1H), 7.72 (s, 1H), 7.42-7.18 (m, 9H),    6.49 (br s, 1H), 5.02-4.92 (m, 1H), 4.84-4.72 (m, 1H), 4.69 (br s,    1H), 3.95 (dd, J=13 Hz, 6 Hz, 1H), 3.42-3.30 (m, 3H), 1.73-1.59 (m,    1H), 1.54-1.43 (m, 1H), 1.42 (d, J=7 Hz, 3H), 1.35-1.17 (m, 4H),    1.01 (br s, 6H), 0.79 (t, J=6 Hz, 3H). ES-LCMS m/z 547 (M+H) HRMS    C₃₁H₃₈N₄O₅ m/z 547.2920 (M+)_(Cal.) 547.2920 (M+H)_(Obs).

Example 22(3S)-1-(1H-1,2,3-Benzotriazol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-7-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-(1H-1,2,3-Benzotriazol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(5 mg, 6%) was obtained as a white solid that contained ethyl acetate(0.18 eq. based on integration of signals in the ¹H NMR spectrum) in twosteps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and1H-1,2,3-benzotriazole-5-carboxylic acid (22 mg, 0.13 mmol) followingthe procedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆,Temp=100° C.) δ 8.76-8.68 (m, 1H), 8.07-7.99 (m, 1H), 7.96-7.87 (m, 1H),7.68-7.52 (m, 1H), 7.35-7.18 (m, 6H), 5.02-4.92 (m, 1H), 4.85-4.67 (m,2H), 3.95 (dd, J=13 Hz, 6 Hz, 1H), 3.43-3.30 (m, 3H), 1.72-1.58 (m, 1H),1.56-1.43 (m, 1H), 1.42 (d, J=7 Hz, 3H), 1.35-1.17 (m, 4H), 1.02 (br s,6H), 0.87-0.74 (m, 3H). ES-LCMS m/z 549 (M+H) HRMS C₂₉H₃₆N₆₀s m/z549.2825 (M+H)_(Cal.) 549.2819 (M+H)_(Obs).

Example 23(3S)-4,4Dimethyl-1-[(3-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-[(3-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(41 mg, 53%) was obtained as a colorless gum that contained ethylacetate (0.4 eq. based on integration of signals in the ¹H NMR spectrum)in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and(3-phenoxyphenyl)acetic acid (30 mg, 0.13 mmol) following the procedureoutlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ8.78-8.68 (m, 1H); 8.07-7.99 (m, 1H); 7.39-7.21 (m, 9H); 7.11 (m₁ 1H);7.03-6.97 (m, 3H); 6.90 (br s, 1H); 6.86 (d, J=9 Hz, 1H); 5.01-4.91 (m,1H); 4.81-4.63 (m, 2H); 3.91-3.83 (m) and 3.72-3.64 (m) total 1H, 3.59(br s, 2H); 3.39-3.10 (m, 3H); 1.71-1.59 (m, 1H); 1.55-1.43 (m, 1H);1.44 (d, J=7 Hz, 3H); 1.34-1.17 (m, 4H); 0.99 (br s, 3H); 0.96 (s, 3H);0.82-0.78 (m, 3H). ES-LCMS m/z 614 (M+H) HRMS C₃₆H₄₃N₃O₆ m/z 614.3230(M+)_(Cal.) 614.3239 (M+H)_(Obs).

Example 24 (3S)-4,4-Dimethyl-1-(4-phenylbutanoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-(4-phenylbutanoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(46 mg, 67%) was obtained as a colorless gum that contained ethylacetate (0.26 eq. based on integration of signals in the ¹H NMRspectrum) in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and 4-phenylbutanoic acid(22 mg, 0.13 mmol) following the procedure outlined in example 21. ¹HNMR (300 MHz, DMSO-d₆, Temp=100° C.) 88.76-8.67 (m, 1H); 7.34-7.13 (m,11H); 5.01-4.91 (m, 1H); 4.82-4.72 (m, 1H); 4.72-4.62 (m, 1H); 3.84-3.75(m) and 3.71-3.60 (m) total 1H, 3.31-3.10 (m, 3H); 2.64-2.58 (m, 2H);2.26-2.16 (m, 2H); 1.88-1.78 (m, 2H); 1.73-1.59 (m, 1H); 1.57-1.44 (m,1H); 1.44 (d, J=7 Hz, 3H); 1.35-1.17 (m, 4H); 1.00 (br s, 36H); 0.99 (s,3H); 0.83-0.78 (m, 3H). ES-LCMS m/z 550 (M+H) HRMS C₃₂H₄₃N₃O₅ m/z550.3281 (M+H)_(Cal.) 550.3274 (M+H)_(Obs).

Example 25(3S)-1-[(4tert-Butylphenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-[(4-tert-Butylphenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(34 mg, 46%) was obtained as a colorless gum that contained ethylacetate (0.4 eq. based on integration of signals in the ¹H NMR spectrum)in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and(4tert-butylphenyl)acetic acid (25 mg, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.75-8.67 (m, 1H); 7.35-7.103 (m, 10H); 5.01-4.91 (m, 1H);4.81-4.64 (m, 2H); 3.99-3.87 (m) and 3.77-3.65 (m) total 1H, 3.54 (m,2H); 3.45-3.12 (m, 3H); 1.73-1.60 (m, 1H); 1.55-1.44 (m, 1H); 1.44 (d,J=7 Hz, 3H); 1.35-1.18 (m, 4H); 1.27 (s, 9H); 1.00 (br s, 36H); 0.97 (s,3H); 0.85-0.78 (m, 3H). ES-LCMS m/z 578 (M+H) HRMS C₃₄H₄₇N₃O₅ m/z578.3594 (M+H)_(Cal.) 578.3580 (M+H)_(Obs).

Example 26(3S)-4,4-Dimethyl-1-{[2-(4-pyridinyl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4Dimethyl-1-{[2-(4-pyridinyl)-1,3-thiazol-4yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (9 mg, 10%)was obtained as a colorless gum that contained ethyl acetate (0.43 eq.based on integration of signals in the ¹H NMR spectrum) in two stepsfrom(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and2-(4-pyridinyl)-1,3-thiazole-4-carboxylic acid (27 mg, 0.13 mmol)following the procedure outlined in example 21, except that the eluentused for the final chromatographic purification was 15% acetone indichloromethane. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 8.72 (d, J=6Hz, 1H), 8.72-8.62 (m, 1H), 8.36 (s, 1H), 7.88 (d, J=6 Hz, 2H),7.37-7.15 (m, 6H), 5.00-4.90 (m, 1H), 4.84-4.71 (m, 2H), 4.42-4.21 (m,1H), 4.05-3.32 (m, 3H); 1.71-1.59 (m, 1H), 1.56-1.42 (m, 1H), 1.41 (d,J=7 Hz, 3H), 1.35-1.16 (m, 4H), 1.07 (br s, 6H), 0.89-0.73 (m, 3H).ES-LCMS m/z 592 (M+H) HRMS C₃₁H₃₇N₅O₅S m/z 592.2593 (M+H)_(Cal.)592.2607 (M+H)_(Obs).

Example 27(3S)-4,4-Dimethyl-1-[(5-methyl-3-phenyl-4-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4Dimethyl-1-[(5-methyl-3-phenyl-4-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (17 mg,23%) was obtained as a colorless gum that contained ethyl acetate (0.3eq. based on integration of signals in the ¹H NMR spectrum) in two stepsfrom (3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and5-methyl-3-phenyl-4-isoxazolecarboxylic acid (27 mg, 0.13 mmol)following the procedure outlined in example 21. ¹H NMR (300 MHz,DMSO-d₆, Temp=100° C.) δ 8.76-8.64 (m, 1H), 7.65-7.58 (m, 2H), 7.61-7.46(m, 3H), 7.71-7.35 (m, 6H), 5.01-4.92 (m, 1H), 4.82-4.52 (m, 2H),4.00-3.80 (m, 1H), 3.56-3.20 (m, 3H), 2.45 (s, 3H), 1.70-1.57 (m, 1H),1.54-1.40 (m, 1H), 1.43 (d, J=7 Hz, 3H), 1.34-1.14 (m, 4H), 1.06-0.75(m, 9H). ES-LCMS m/z 589(M+H) HRMS C₃₃H₄₀N₄O₆ m/z 589.3026 (M+H)_(Cal.)589.3036 (M+H)_(Obs).

Example 28(3S)-4,4-Dimethyl-7-[(1-methyl-1H-indol-2-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4Dimethyl-1-[(1-methyl-1H-indol-2-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(34 mg, 47%) was obtained as a yellow gum that contained ethyl acetate(0.5 eq. based on integration of signals in the ¹H NMR spectrum) in twosteps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and1-methyl-1H-indole-2-carboxylic acid (23 mg, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.71 (d, J=8 Hz, 1H), 7.62 (m, 1H), 7.47 (dd, J=8 Hz, 1 Hz, 1H),7.34-7.18 (m, 7H), 7.11-7.06 (m, 1H), 6.78 (s, 1H), 5.01-4.91 (m, 1H),4.82-4.71 (m, 2H), 4.05-3.99 (m, 1H), 3.82 (s, 3H), 3.02-2.86 (m, 3H),1.72-1.60 (m, 1H), 1.57-1.45 (m, 1H), 1.42 (d, J=7 Hz, 3H), 1.35-1.17(m, 4H), 1.05 (s, 6H), 0.82-0.77 (m, 3H). ES-LCMS m/z 561 (M+H) HRMSC₃₂H₄₀N₄O₅ m/z 561.3077 (M+H)_(Cal.) 561.3096 (M+H)_(Obs).

Example 29 (3S)-4,4-Dimethyl-(3-quinolinylcarbonyl)pyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4Dimethyl-1-(3-quinolinylcarbonyl)pyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (36 mg, 54%) wasobtained as a colorless gum in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and 3-quinolinecarboxylicacid (23 mg, 0.13 mmol) following the procedure outlined in example 21,except that the eluent used for the final chromatographic purificationwas 150/acetone in dichloromethane. ¹H NMR (300 MHz, DMSO-d₆, Tem p=100°C.) δ 8.98 (d, J=2 Hz, 1H), 8.76-8.66 (m, 1H), 8.51 (s, 1H), 8.08-8.03(m, 2H), 7.86-7.80 (m, 1H), 7.69-7.64 (m, 1H), 7.34-7.18 (m, 6H),5.01-4.90 (m, 1H), 4.83-4.70 (m, 2H), 4.02 (dd, J=13 Hz, 5 Hz, 1H),3.60-3.38 (m, 3H), 1.73-1.58 (m, 1H), 1.55-1.47 (m, 1H), 1.42 (d, J=7Hz, 3H), 1.35-1.17 (m, 4H), 1.13-0.99 (m, 6H), 0.840.74 (m, 3H). ES-LCMSm/z 559 (M+H) HRMS C₃₂H₃₈N₄O₅ m/z 559.2920 (M+H)_(Cal.) 559.2931(M+H)_(Obs).

Example 30 (3S)-1-([1,1′-Biphenyl]-4-ylacetyl)-4,4-dimethylpyrrolidinyl(15)-1-(oxo {[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-([1,1′-Biphenyl]-4-ylacetyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(46 mg, 60%) was obtained as a colorless gum that contained ethylacetate and acetic acid (0.36 eq. and 0.16 eq. respectively, based onintegration of signals in the ¹H NMR spectrum) in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and[1,1′-biphenyl]-4-ylacetic acid (28 mg, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.76-8.67 (m, 1H); 7.63-7.56 (m, 2H); 7.43 (m, 2H); 7.36-7.17 (m,9H); 5.02-4.92 (m, 1H); 4.82-4.65 (m, 2H); 3.99-3.90 (m) and 3.76-3.69(m) total 1H, 3.64 (br s, 2H); 3.50-3.18 (m, 3H); 1.73-1.58 (m, 1H);1.56-1.44 (m, 1H); 1.44 (d, J=7 Hz, 3H); 1.33-1.17 (m, 4H); 1.01 (s,3H); 0.99 (s, 3H); 0.82-0.78 (m, 3H). ES-LCMS m/z 598 (M+H) HRMSC₃₆H₄₃N₃O₅ m/z 598.3281 (M+H)_(Cal.) 598.3281 (M+H)_(Obs).

Example 31 (3S)-4,4-Dimethyl-1-[(2-phenoxyphenyl)acetyl]pyrrolidinyl(1s)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4Dimethyl-1-[(2-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (25 mg, 32%) wasobtained as a colorless gum that contained ethyl acetate and acetic acid(0.2 eq. of each, based on integration of signals in the ¹H NMRspectrum) in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and(2-phenoxyphenyl)acetic acid (0.030 g, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.76-8.66 (m, H); 7.37-7.05 (m. 12H); 6.92 (d, J=8 Hz, 2H); 6.84(d, J=6 Hz, 1H); 5.02-4.92 (m, 1H); 4.81-4.71 (m, 1H); 4.70-4.59 (m,1H); 3.88-3.77 (m) and 3.70-3.48 (m) total 3H, 3.39-3.08 (m, 3H);1.71-1.59 (m, 1H); 1.56-1.44 (m, 1H); 1.44 (d, J=7 Hz, 3H); 1.33-1.17(m, 4H); 0.96 (s, 3H); 0.92 (s, 3H); 0.83-0.78 (m, 3H). ES-LCMS m/z 614(M+H) HRMS C₃₆H₄₃N₃O₆ m/z 614.3230 (M+H)_(Cal.) 614.3231 (M+H)_(Obs).

Example 32(3S)-1-(1H-Indol-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-(1H-Indol-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(10 mg, 14%) was obtained as a yellow glass that contained ethyl acetateand acetic acid (0.07 eq. and 0.34 eq. respectively, based onintegration of signals in the ¹H NMR spectrum) in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and1H-indole-2-carboxylic acid (21 mg, 0.13 mmol) following the procedureoutlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 11.21(br s, 1H), 8.72-8.66 (m, 1H), 7.62 (d J=8 Hz, 1H), 7.46 (d J=9 Hz, 1H),7.34-7.16 (m, 7H), 7.06-7.01 (m, 1H), 6.92 (s, 1H), 5.00-4.90 (m, 1H),4.83-4.76 (m, 2H), 4.18-4.02 (m, 1H), 3.70-3.50 (m, 3H), 1.72-1.59 (m,1H), 1.57-1.43 (m, 1H), 1.40 (d, J=7 Hz, 3H), 1.33-1.17 (m, 4H), 1.09(s, 3H), 1.07 (s, 3H), 0.81-0.77 (m, 3H). ES-LCMS m/z 547 (M+H) HRMSC₃₁H₃₈N₄O₅ m/z 547.2920 (M+H)_(Cal.) 547.2922 (M+H)_(Obs).

Example 33 (3S)-4,4-Dimethyl-1-(3-pyridinylacetyl)pyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-(3-pyridinylacetyl)pyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (31 mg, 47%) wasobtained as a colorless gum that contained ethyl acetate (0.35 eq. basedon integration of signals in the ¹H NMR spectrum) in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and 3-pyridinylaceticacid hydrochloride (23 mg, 0.13 mmol) following the procedure outlinedin example 21, except that 3-(morpholino)propylpolystyrenesulfonamide(50 mg, 2.03 mmol/g, 0.10 mmol) was added to the acid prior to theaddition of the 1-hydroxybenzotriazole solution. A solution of 30%acetone in dichloromethane was used as eluent in the finalchromatographic purification. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ8.76-8.68 (m, H); 8.42 (br s, 2H); 7.61 (m, 1H); 7.37-7.15 (m, 7H);5.02-4.91 (m, 1H); 4.86-4.63 (m, 2H); 4.01-3.91 (m) and 3.78-3.66 (m)total 3H, 3.50-3.10 (m, 3H); 1.79-1.61 (m, 1H); 1.56-1.44 (m, 1H); 1.44(d, J=7 Hz, 3H); 1.38-1.15 (m, 4H); 1.02 (s) 1.00 (s), and 0.98 (s)total 3H, 0.90-0.78 (m, 3H). ES-LCMS m/z 523 (M+H) HRMS C₂₉H₃₈N₄O₅ m/z523.2920 (M+)_(Cal.) 523.2924 (M+H)_(Obs).

Example 34(3S)-4,4-Dimethyl-1-(1H-1,2,4-triazol-3-ylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-(1H-1,2,4-triazol-3-ylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(20 mg, 30%) was obtained in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and1H-1,2,4-triazole-3-carboxylic acid (0.014 g, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.71 (m, 1H), 7.36-7.18 (m, 7H), 4.96 (qnt, J=8 Hz, 1H), 4.83-4.39(m, 2H), 4.22 (m, 1H), 3.91 (m, 1H), 3.67 (m, 1H), 3.47 (m, 1H), 3.35(m, 1H), 1.64 (m, 1H), 1.48 (m, 1H), 1.43 (d, J=7 Hz, 3H), 1.20 (m, 4H),1.03 (m, 6H), 0.79 (m, 3H). ES-LCMS m/z 499 (M+H) HRMS C₂₅H₃₄N₆O₅ m/z521.2488 (M+Na)_(Cal.) 521.2501 (M+Na)_(Obs).

Example 35(3S)-4,4-Dimethyl-1-[(3-methyl-5-isoxazolyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-[(3-methyl-5-isoxazolyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(18 mg, 26%) was obtained in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and(3-methyl-5-isoxazolyl)acetic acid (0.017 g, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.72 (m, 1H), 7.38-7.18 (m, 6H), 3.16 (s, 1H), 4.97 (qnt, J=8 Hz,1H), 4.85-4.60 (m, 2H), 3.93 (m, 1H), 3.79 (s, 2H), 3.55-3.20 (m, 3H),2.19 (s, 3H), 1.70 (m, 1H), 1.50 (m, 1H), 1.44 (d, J=7 Hz, 3H), 1.27 (m,4H), 1.02 (s, 6H), 0.82 (t, J=7 Hz, 3H); ES-LCMS m/z 549 (M+H) HRMSC₂₈H₃₈N₄O₆ m/z 549.2689 (M+Na)_(Cal.) 549.2697 (M+H)_(Obs).

Example 36(3S)-1-(1H-Indazol-3-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-(1H-Indazol-3-ylcarbonyl)-4,4-dimethylpyrrolidinyl(15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (25 mg,35%) was obtained in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL; 120 mM in dichloromethane, 0.12 mmol) and1H-indazole-3-carboxylic acid (0.019 g, 0.13 mmol) following theprocedure outlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 13.27 (s, 1H), 8.68 (m, 1H), 8.15 (d, J=8 Hz, 1H), 7.58 (d, J=8Hz, 1H), 7.39 (t, J=7 Hz, 1H), 7.33-7.16 (m, 6H), 4.94 (m, 1H), 4.77 (m,2H), 4.32 (m, 1H), 3.96 (m, 1H), 3.76 (m, 1H), 3.50 (m, 2H), 1.65 (m,1H), 1.48 (m, 1H), 1.41 (d, J=7 Hz, 3H), 1.25 (m, 4H), 1.07 (m, 6H),0.78 (m, 3H); ES-LCMS m/z 570 (M+Na) HRMS C₃₀H₃₇N₅O₅ m/z 548.2873(M+H)_(Cal.) 548.2867 (M+H)_(Obs).

Example 37(3S)-4,4-Dimethyl-1-{[2-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-{[2-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1phenylethyl]amino}acetyl)pentylcarbamate(25 mg, 350%) was obtained in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and2-(4methyl-1,2,3-thiadiazol-5-yl)-1,3-thiazole-4-carboxylic acid (0.027g, 0.13 mmol) following the procedure outlined in example 21. ¹H NMR(300 MHz, DMSO-d₆, Temp=100° C.) δ 8.69 (m, 1H), 8.48 (s, 1H), 7.37-7.15(m, 6H), 4.95 (m, 1H), 4.77 (m, 2H), 4.22 (m, 1H), 4.10-3.60 (m, 3H),3.47 (m, 2H), 2.95 (s, 3H) 1.65 (m, 1H), 1.50 (m, 1H), 1.42 (d, J=7 Hz,3H), 1.25 (m, 4H), 1.06 (m, 6H), 0.78 (m, 3H). ES-LCMS m/z 635 (M+Na)HRMS C₃₆H₄₃N₃O₆ m/z 635.2086 (M+H)_(Cal.) 635.2106 (M+H)_(Obs).

Example 38(3S)-4,4-Dimethyl-1-{[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetyl-}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-{[2-(2-pyrazinyl)-1,3-thiazol-4yl]acetyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (17 mg,210/0) was obtained in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12 mmol) and[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetic acid (0.027 g, 0.13 mmol)following the procedure outlined in example 21. ¹H NMR (300 MHz,DMSO-d₆, Temp=100° C.) δ 9.24 (s, 1H), 8.67 (m, 3H), 7.61 (s, 1H),7.35-7.10 (m, 6H), 4.97 (qnt, J=7 Hz, 1H), 4.83-4.65 (m, 2H), 4.06 (m,1H), 3.86 (s, 2H), 3.80-3.20 (m, 3H), 1.65 (m, 1H), 1.50 (m, 1H), 1.44(d, J=7 Hz, 3H), 1.26 (m, 4H), 1.03 (m, 6H), 0.80 (t, J=7 Hz, 3H).ES-LCMS m/z 629 (M+Na) HRMS C₃₁H₃₈N₆O₅S₁ m/z 607.2703 (M+H)_(Cal.)607.2723 (M+H)_(Obs).

Example 39(3S)-1-[(4-Fluorophenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-7-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-[(4-Fluorophenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(16 mg, 22%) was obtained in two steps from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(1.0 mL, 120 mM in dichloromethane, 0.12-mmol) and(4-fluorophenyl)acetic acid (0.018 g, 0.13 mmol) following the procedureoutlined in example 21. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 8.70(m, 1H); 7.35-7.18 (m, 8H); 7.07 (t, J=9 Hz, 2H); 4.97 (qnt, J=8 Hz,1H); 4.82-4.60 (m, 2H); 3.87 (m) and 3.66 (m) total 1H, 3.58 (s, 2H);3.45-3.10 (m, 3H); 1.64 (m, 1H); 1.50 (m, 1H); 1.44 (d, J=7 Hz, 3H);1.26 (m, 4H); 0.99 (d, J=6 Hz, 6H); 0.81 (t, J=7 Hz, 3H). Cl-LCMS m/z540 (M+H) HRMS C₃₀H₃₈N₃O₅ m/z 540.2874 (M+H)_(Cal.) 540.2874(M+H)_(Obs).

Example 40 [1,1′-biphenyl]-4-ylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

To a solution of 0.14 mL (0.27 mmol) of 1.93M phosgene in toluene in 1mL of dichloromethane was added 25 mg (0.14 mmol) of 4-biphenylmethanol,and the reaction mixture was stirred at room temperature for 18 h. For10 min a stream of nitrogen was passed through the reaction mixture,which was then added to a solution of 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 0.038 mL (0.27 mmol) of triethylamine in 2 mL of dichloromethane.The resulting reaction mixture was stirred for 3 h before 25 mg oftris-(2-aminoethyl)amine polystyrene was added. The resulting mixturewas then shaken for 2 h. Dowex 50W×4(H⁺) resin (1.0 g) was added and themixture was shaken for 1 h. The solids were filtered off and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in 2 mL of dichloromethane before 19 mg (0.23 mmol) of sodiumbicarbonate and 97 mg (0.23 mmol) of Dess-Martin periodinane were added.The reaction mixture was stirred for 20 min and then subjected directlyto column chromatography on silica gel. Elution with 0.5:9.5acetone:dichloromethane afforded 60 mg (79%) of [1,1′-biphenyl]-4ylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate.¹H NMR (300 MHz, DMSO-d₆, Temp=80° C.) δ 8.87 (d, J=7 Hz, 1H), 7.68 (d,J=8 Hz, 3H), 7.47 (d, J=8 Hz, 3H), 7.41-7.20 (m, 9H), 5.15 (s, 2H), 4.99(qnt, J=7 Hz, 1H), 4.80 (m, 1H), 4.70 (s, 1H), 3.76 (m, 1H), 3.24 (m,3), 1.67 (m, 1H), 1.51 (m, 1H), 1.46 (d, J=7 Hz, 3H), 1.27 (m, 4H), 1.05(s, 6H), 0.83 (t, J=7 Hz, 3H). ES-LCMS m/z 614 (M+H) HRMS C₃₆H₄₃N₃O₆ m/z668.3312 (M+Na+MeOH)_(Cal.) 668.3312 (M+Na⁺MeOH)_(Obs).

Example 41 Tetrahydro-2-furanylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

Tetrahydro-2-furanylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(16 mg, 22%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 14 mg (0.14 mmol) of tetrahydrofurfuryl alcohol following theprocedure outlined in example 40. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 8.76 (m, 1H), 7.42-7.20 (m, 6H), 5.01 (qnt, J=7 Hz, 1H), 4.81 (m,1H), 4.69 (d, J=3 Hz, 1H), 4.01 (m, 3H), 3.83-3.64 (m, 3H), 3.32-3.15(m, 3H), 2.00-1.80 (m, 3H), 1.75-1.58 (m, 3H), 1.48 (d, J=7 Hz, 3H),1.30 (m, 4H), 1.04 (s, 6H), 0.85 (t, J=7 Hz, 3H). ES-LCMS m/z 532 (M+H)HRMS C₂₈H₄₁N₃O₇ m/z 532.3023 (M+H)_(Cal.) 532.3023 (M+H)_(Obs).

Example 42 3-Thienylmethyl (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

3-Thienyl methyl(4S)-3,3-dimethyl-4[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(35 mg, 52%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 16 mg (0.14 mmol) of 3-thienylmethanol following the procedureoutlined in example 40. ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (d, J=9 Hz,1H), 7.65 (m, 1H), 7.50 (m, 1H), 7.34-7.19 (m, 5H), 7.10 (m, 1H), 5.03(s, 2H), 4.94 (qnt, J=7 Hz, 1H), 4.73 (m, 1H), 3.71 (m, 1H), 3.17 (m,3H), 1.60 (m, 1H), 1.45-1.13 (m, 8H), 0.97 (s, 6H), 0.77 (m, 3H).ES-LCMS m/z 544 (M+H) HRMS C₂₈H₃₇N₃O₆S₁ m/z 566.2301 (M+Na)_(Cal.)566.2300 (M+Na)_(Obs).

Example 43 (3S)-Tetrahydro-3-furanyl(4S)-3,3-dimethyl-4-[({[(1S)-7-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

(3S)-Tetrahydro-3-furanyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(35 mg, 550%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl-(S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 12 mg (0.14 mmol) of (3S)-tetrahydro-3-furanol following theprocedure outlined in example 40. ¹H NMR (300 MHz, DMSO-d₆, Temp=100°C.) δ 9.15 (d, J=8 Hz, 1H), 7.66 (m, 1H), 7.35-7.17 (m, 5H), 5.09 (m,1H), 4.96 (qnt, J=7 Hz, 1H), 4.74 (m, 1H), 4.64 (m, 1H), 3.80-3.61 (m,5H), 3.25-3.02 (m, 3H), 2.07 (m, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.40(d, J=7 Hz, 3H), 1.24 (m, 5H), 0.96 (s, 6H), 0.78 (m, 3H). ES-LCMS m/z518 (M+H) HRMS C₂₇H₃₉N₃O₇ m/z 518.2866 (M+H)Cal. 518.2863 (M+H)_(Obs).

Example 44 Benzyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

Benzyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(27 mg, 41%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 25 mg (0.15 mmol) of benzyloxychloroformate following the procedureoutlined in example 40. ¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (d, J=8 Hz,1H), 7.62 (m, 1H), 7.38-7.14 (m, 10H), 5.00 (s, 2H), 4.90 (m, 1H), 4.69(m, 1H), 4.62 (d, J=3 Hz, 1H), 3.68 (m, 1H), 3.25-3.05 (m, 3H), 1.55 (m,1H), 1.36 (m, 4H), 1.20 (m, 4H), 0.94 (m, 6H), 0.73 (m, 3H). ES-LCMS m/z538 (M+H) HRMS C₃₀H₃₉N₃O₆ m/z 538.2917 (M+H)_(Cal.) 538.2935(M+H)_(Obs).

Example 45 2-Phenylethyl (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

2-Phenylethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(12 mg, 17%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 18 mg (0.14 mmol) of 2-phenylethanol following the procedureoutlined in example 40. ¹H NMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 8.74(m, 1H), 7.38-7.20 (m, 11H), 5.02 (qnt, J=8 Hz, 1H), 4.80 (m, 1H), 4.67(m, 1H), 4.23 (t, J=7 Hz, 2H), 3.67 (m, 1H), 3.25-2.90 (m, overlappingwater peak 5H), 1.67 (m, 1H), 1.53 (m, 1H), 1.48 (d, J=7 Hz, 3H), 1.29(m, 4H), 1.01 (s, 6H), 0.84 (t, J=7 Hz, 3H). Cl-LCMS m/z 552 (M+H); HRMSC₃₁H₄₁N₃O₆ m/z 574.2893 (M+Na)_(Cal.) 574.2897 (M+H)_(Obs).

Example 46 (1-Phenyl-1H-1,2,3-triazol-4-yl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

(1 Phenyl 1H-1,2,3-triazol-4-ylmethyl-(4S)3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(20 mg, 27%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 24 mg (0.14 mmol) of (1-phenyl-1H-1,2,3-triazol-4-yl)methanolfollowing the procedure outlined in example 40 except that Dowex50W×4(H+) resin was not utilized. ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (d,J=7 Hz, 1H), 8.79 (s, 1H), 7.85 (m, 2H), 7.57 (m, 3H), 7.44 (m, 1H),7.28-7.15 (m, 5H), 5.14 (s, 2H), 4.90 (m, 1H), 4.68 (m, 1H), 4.62 (s,1H), 3.68 (m, 1H), 3.40-3.06 (m, 3H), 1.53 (m, 1H), 1.35 (m, 4H), 1.18(m, 4H), 0.94 (m, 6H), 0.73 (m, 3H). ES-LCMS m/z 605 (M+H) HRMSC₃₂H₄₀N₆O₆ m/z 605.3087 (M+)_(Cal.) 605.3083 (M+H)_(Obs).

Example 47 2-(2-Oxo-1-pyrrolidinyl)ethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

2-(2-Oxo-1-pyrrolidinyl)ethyl (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{{[(R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(30 mg, 44010) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 18 mg (0.14 mmol) of 1-(2-hydroxyethyl)-2-pyrrolidinone followingthe procedure outlined in example 40 except that Dowex 50W×4(H⁺) resinwas not utilized. ¹H NMR (400 MHz, DMSO-d₆) δ 6.12 (d, J=8 Hz, 1H), 7.60(m, 1H), 7.30-7.14 (m, 5H), 4.90 (qnt, J=7 Hz, 1H), 4.70 (m, 1H), 4.60(d, J=4 Hz, 1H), 4.09-3.95 (m, 2H), 3.62 (m, 1H), 3.25 (m, overlappingwater peak 4H), 3.20-2.95 (m, 3H), 2.13 (m, 2H), 1.85 (m, 2H), 1.55 (m,1H), 1.36 (d, J=7 Hz, 3H), 1.34 (m, 1H), 1.19 (m, 4H), 0.93 (s, 6H),0.74 (m, 3H). ES-LCMS m/z 559 (M+H) HRMS C₂₉H₄₂N₄O₇ m/z 559.31-32(M+H)_(Cal.) 559.3151 (M+H)_(Obs).

Example 48 Tetrahydro-2H-pyran-2-ylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

Tetrahydro-2H-pyran-2-yl methyl (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(12 mg, 24%) was obtained in two steps from 50 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 17 mg (0.14 mmol) of tetrahydro-2H-pyran-2-ylmethanol following theprocedure outlined in example 40. ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (d,J=8 Hz, 1H), 7.70 (m, 1H), 7.37-7.20 (m, 5H), 4.99 (m, 1H), 4.78 (m,1H), 4.68 (m, 1H), 3.97-3.81 (m, 2H), 3.71 (m, 1H), 3.25 under waterpeak (m, 3H), 3.20 (m, 3H), 1.79 (m, 1H), 1.50 (m, 10H), 1.26 (m, 4H),1.02 (m, 6H), 0.83 (m, 3H). ES-LCMS m/z 546 (M+H) HRMS C₂₉H₄₃N₃O₇ m/z546.3179 (M+H)_(Cal.) 546.3169 (M+H)_(Obs).

Example 49 Tetrahydro-3-furanylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

Tetrahydro-3-furanylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate (8 mg, 120%) wasobtained in two steps from 50 mg (0.12 mmol) of (3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 15 mg (0.14 mmol) of tetrahydro-3-furanylmethanol following theprocedure outlined in example 40. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (d,J=9 Hz, 1H), 7.66 (m, 1H), 7.35-7.20 (m, 5H), 4.96 (qnt, J=8 Hz, 1H),4.75 (m, 1H), 4.66 (m, 1H), 3.93 (m, 2H), 3.67 (m, 5H), 3.25 (m,overlapping water peak 3H), 1.92 (m, 2H), 1.57 (m, 3H), 1.41 (d, J=7 Hz,3H), 1.23 (m, 4H), 0.99 (s, 6H), 0.82 (m, 3H). Cl-LCMS m/z 532 (M+H).

Example 50 [3-Methyl-5-(5-methyl-isoxazol-3-yl)-4-isoxazolyl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

To a solution of 26 mg (0.14 mmol) of[3-methyl-5-(5-methyl-3-isoxazolyl)-4-isoxazolyl]methanol in 1 mL oftetrahydrofuran was added 0.28 mL of phosgene (1.93M in toluene, 0.54mmol), and the reaction mixture was stirred at room temperature for 18h. A stream of nitrogen was passed through the solution for 15 minutesbefore a solution of 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 0.076 mL (0.54 mmol) of triethylamine in 2 mL of tetrahydrofuran wasadded. The reaction mixture was shaken for 18 h and then filtered. Dowex50W×4(H⁺) resin was added to the filtrate, and the mixture was shakenfor 1 h. Solids were filtered off, and the filtrate was concentratedunder a stream of nitrogen. The residue was dissolved in 2 mL ofdichloromethane, and 50.0 mg (0.59 mmol) of sodium bicarbonate and100-mg (0.23 mmol) of Dess-Martin periodinane were added. The reactionmixture was stirred for 30 minutes before being washed with 2 mL ofsaturated aqueous sodium thiosulfate. The organic phase wasconcentrated, and the residue was purified by silica gel column, elutingwith 1.5:8.5 acetone: dichloromethane to afford 15 mg (188%) of[3-methyl-5-(5-methyl-isoxazol-3-yl)-4-isoxazolyl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate.¹H NMR (300 MHz, DMSO-d₆, Temp=80° C.) δ 9.34 (d, J=8 Hz, 1H), 7.81 (t,J=7 Hz, 1H), 7.52-7.36 (m, 5H), 7.00 (d, J=4 Hz, 1H), 5.35 (s, 2H), 5.13(m, 1H), 4.91 (m, 1H), 4.82 (m, 1H), 3.68 (m, 1H), 3.50-3.15 (m, 3H),2.68 (m, 6H), 1.77 (m, 1H), 1.65-1.30 (m, 8H), 1.40 (m, 6H), 0.96 (m,3H). ES-LCMS m/z 624 (M+H) HRMS C₃₂H₄₁N₅O₈ m/z 646.2853 (M+Na)_(Cal.)646.2853 (M+H)_(Obs).

Example 51 2-(4-Methyl-1,3-thiazol-5-yl)ethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

2-(4-Methyl-1,3-thiazol-5-yl)ethyl(4S)-3,3-dimethyl-4[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(8 mg, 11%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 26 mg (0.14 mmol) of 2-(4-methyl-1,3-thiazol-5-yl)ethanol followingthe procedure outlined in example 50. ¹H NMR (300 MHz, DMSO-d₆) δ 9.35(d, J=8 Hz, 1H), 9.01 (d, J=7 Hz, 1H), 7.83 (t, J=7 Hz, 1H), 7.52-7.36(m, 5H), 5.14 (qnt, J=8 Hz, 1H), 4.93 (m, 1H), 4.83 (m, 1H), 4.30 (m,2H), 3.85 (m, 1H), 3.50-3.20 (m, 5H), 2.67 (s, 3H), 1.77 (m, 1H),1.65-1.30 (m, 8H), 1.16 (m, 6H), 0.97 (m, 3H). ES-LCMS m/z 573 (M+H)HRMS C₂₉H₄₀N₄O₆S₁ m/z 573.2747 (M+H)_(Cal.) 573.2731 (M+Na)_(Obs).

Example 52 (5-methyl-3-isoxazolyl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

(5-Methyl-3-isoxazolyl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(42 mg, 57%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 15 mg (0.14 mmol) of (5-methyl-3-isoxazolyl)methanol following theprocedure outlined in example 50. ¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (d,J=8 Hz, 1H), 7.84 (dd, J=7 Hz, J=5 Hz, 1H), 7.52-7.35 (m, 5H), 6.43 (s,1H), 5.23 (s, 1H), 5.13 (m, 1H), 4.92 (m, 1H), 4.85 (d, J=4 Hz, 1H),3.91 (m, 1H), 3.50-3.25 (m, 3H), 2.67 (s, 3H), 1.78 (m, 1H), 1.65-1.30(m, 8H), 1.17 (s, 6H), 0.96 (t, J=7 Hz, 3H). ES-LCMS m/z 543 (M+H) HRMSC₂₈H₃₈N₄O₇ m/z 565.2638 (M+)_(Cal.) 565.2638 (M+Na)_(Obs).

Example 53 [3-(2,6-Dichlorophenyl)-5-methyl-4-isoxazolyl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

[3-(2,6-Dichlorophenyl)-5-methyl-4 isoxazolyl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(59 mg, 70%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 35 mg (0.14 mmol) of [3-(2,6-dichlorophenyl)-5-methyl-4isoxazolyl]methanol following the procedure outlined in example 50. ¹HNMR (300 MHz, DMSO-d₆) δ 9.34 (d, J=8 Hz, 1H), 7.86-7.73 (m, 4H),7.51-7.36 (m, 5H), 5.12 (qnt, J=7 Hz, 1H), 4.94 (m, 3H), 4.74 (t, J=5Hz, 1H), 3.77 (m. 1H), 3.30-3.00 (m, 3H), 2.72 (s, 3H), 1.78 (m, 1H),1.62-1.30 (m, 8H), 1.10 (m, 6H), 0.96 (m, 3H). ES-LCMS m/z 709 (M+Na)HRMS C₃₄H₄₀N₄O₇Cl₂ m/z 701.2172 (M+H)_(Cal.) 701.2173 (M+Na)_(Obs).

Example 54 (2-Methyl[1,1′-biphenyl]-3-yl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

(2-Methyl [1,1′-biphenyl]-3-yl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(42 mg, 55%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 27 mg (0.14 mmol) of (2-methyl[1,1′-biphenyl]-3-yl)methanolfollowing the procedure outlined in example 50. ¹H NMR (300 MHz,DMSO-d₆) δ 9.16 (d, J=8 Hz, 1H), 7.65 (t, J=7 Hz, 1H), 7.47-7.12 (m,13H), 5.12 (s, 2H), 4.94 (m, 1H), 4.73 (m, 1H), 4.66 (m, 1H), 3.74 (m,1H), 3.50-3.05 (m, 3H), 2.15 (s, 1H), 1.57 (m, 1H), 1.43-1.10 (m, 8H),0.99 (s, 6H), 0.77 (t, J=7 Hz, 3H). ES-LCMS m/z 650 (M+Na) HRMSC₃₇H₄₅N₃O₆ m/z 650.3206 (M+Na)_(Cal.) 650.3207 (M+Na)_(Obs).

Example 55 [5-(2-Thienyl)-1,2,4-oxadiazol-3-yl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

[5-(2-Thienyl)-1,2,4-oxadiazol-3-yl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(40 mg, 51%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 25 mg (0.14 mmol) of [5-(2-thienyl)-1,2,4-oxadiazol-3-yl]methanolfollowing the procedure outlined in example 50 except that the[5-(2-thienyl)-1,2,4-oxadiazol-3-yl]methanol solution was cooled to 0°C. before phosgene was added, and then let warm to room temperature. ¹HNMR (300 MHz, DMSO-d₆) δ 9.17 (d, J=8 Hz, 1H), 8.10 (d, J=5 Hz, 1H),8.04 (s, 1H), 7.68 (t, J=6 Hz, 1H), 7.40-7.15 (m, 6H), 5.25 (s, 2H),4.96 (m, 1H), 4.80-4.67 (m, 2H), 3.75 (m, 1H), 3.50-3.10 (m, 3H), 1.60(m, 1H), 1.41 (d, J=6 Hz, 3H), 1.24 (m, 5H), 1.01 (s, 6H), 0.78 (m, 3H).ES-LCMS m/z 612 (M+H) HRMS C₃₀H₃₇N₅O₇S₁ m/z 634.2311 (M+Na)_(Cal.)634.2317 (M+Na)_(Obs).

Example 56 (3R)-Tetrahydro-3-furanyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

(3R)-Tetrahydro-3-furanyl(4S)-3,3-dimethyl-4[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(28 mg, 44%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4—dimethylpyrrolidinyl(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 12 mg (0.14 mmol) of (3R)-tetrahydro-3-furanol following theprocedure outlined in example 50 except that the(3R)-tetrahydro-3-furanol solution was cooled to O C before phosgene wasadded, and then let warm to room temperature. ¹H NMR (300 MHz, DMSO-d₆)δ 9.17 (d, J=9 Hz, 1H), 7.66 (m, 1H), 7.37-7.19 (m, 5H), 5.11 (m, 1H),4.96 (qnt, J=8 Hz, 1H), 4.75 (m, 1H), 4.66 (d, J=4 Hz, 1H), 3.81-3.60(m, 5H), 3.25-3.02 (m, 3H), 2.15 (m, 1H), 1.88 (m, 1H), 1.66 (m, 1H),1.42 (d, J=7 Hz, 3H), 1.21 (m, 5H), 0.99 (s, 6H), 0.80 (t, J=7 Hz, 3H).ES-LCMS m/z 518 (M+H) HRMS C₂₇H₃₉N₃O₇ m/z 540.2686 (M+Na)_(Cal.)540.2665 (M+Na)_(Obs).

Example 57[1,1′-Biphenyl-4yl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

To a solution of 0.28 mL of phosgene (1.93M in toluene, 0.54 mmol) in 1mL of dichloromethane was added 23 mg (0.14 mmol) of 4-phenylphenol. Thesolution was cooled in an ice 1 mL (0.14 mol) of N,N-dimethylaniline wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature and was stirred for 18 h. A stream of nitrogen was thenpassed through the reaction mixture for 10 minutes before a solution of50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 0.038 mL (0.27 mmol) of triethylamine in 2 mL of tetrahydrofuran wasadded. The reaction mixture was shaken for 1.5 h before 50.0 mg oftris-(2-aminoethyl)amine polystyrene and 1.0 g of Dowex 50W×4(H) resinwere added. The mixture was shaken for 2.5 h. The solids were filteredoff and the filtrate was concentrated under a stream of nitrogen. Theresidue was dissolved in 1 mL of dichloromethane, and 21 mg (0.25 mmol)of sodium bicarbonate and 100 mg (0.25 mmol) of Dess-Martin periodinanewere added. The reaction mixture was stirred for 30 minutes before beingwashed with 2 mL of saturated aqueous sodium thiosulfate. The organicphase was concentrated, and the residue was purified by silica gelchromatography eluting with 1.5:8.5 acetone:dichloromethane to afford 15mg (188%) of [1,1′-biphenyl]-4-yl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate.¹H NMR (300 MHz, DMSO-d₆, Temp=80° C.) 39.17 (d, J=8 Hz, 1H); 7.75-7.62(m, 5H); 7.45 (t, J=8 Hz, 2H); 7.34-7.19 (m, 8H); 4.96 (qnt, J=7 Hz,1H); 4.74 (m, 1H); 3.97 (m) and 3.80 (m) total 1H, 3.55-3.17 (m, 3H);1.61 (m, 1H); 1.41 (d, J=7 Hz, 3H); 1.27 (m, 5H); 1.06 (m, 6H); 0.80 (m,3H). ES-LCMS m/z 600 (M+H) HRMS C₃₅H₄₁N₃O₆ m/z 622.2893 (M+Na)_(Cal.)622.2889 (M+Na)_(Obs).

Example 58 4-Phenoxyphenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

4-Phenoxyphenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(42 mg, 55%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 25 mg (0.14 mmol) of 4-phenoxyphenol following the procedureoutlined in example 57. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (d, J=9 Hz,1H), 7.71 (m, 1H), 7.38 (t, J=8 Hz, 2H), 7.32-7.20 (m, 5H); 7.13 (d, J=9Hz, 3H), 6.99 (d, J=9 Hz, 4H), 4.95 (m, 1H), 7.73 (m, 2H), 3.93-3.75 (m,1H), 3.45-3.15 (m, 3H), 1.59 (m, 1H), 1.40 (d, J=6 Hz, 3H), 1.24 (m,5H), 1.04 (m, 6H), 0.79 (t, J=7 Hz, 3H). Cl-LCMS m/z 638 (M+Na) HRMSC₃₅H₄₁N₃O₇ m/z 638.2842 (M+Na)_(Cal.) 638.2821 (M+Na)_(Obs).

Example 59 3-Phenoxyphenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

3-Phenoxyphenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(20 mg, 26%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 25 mg (0.14 mmol) of 3-phenoxyphenol following the procedureoutlined in example 57. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (d, J=8 Hz,1H); 7.69 (m, 1H); 7.43-7.12 (m, 9H); 7.03 (m, 2H); 6.91-6.75 (m, 3H);4.99 (m, 1H); 4.71 (m, 2H); 3.90 (m) and 3.75 (m) total 1H, 3.45-3.15(m, 3H); 1.60 (m, 1H); 1.40 (d, J=6 Hz, 3H); 1.23 (m, 5H); 1.02 (m, 6H);0.78 (m, 3H). ES-LCMS m/z 638 (M+Na) HRMS C₃₅H₄₁N₃O₇ m/z 638.2842(M+Na)_(Cal.) 638.2859 (M+Na)_(Obs).

Example 60 2-Naphthyl (4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

2-Naphthyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(18 mg, 25%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 25 mg (0.14 mmol) of 2-naphthol following the procedure outlined inexample 57. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (d, J=8 Hz, 1H); 7.95-7.85(m, 3H); 7.77-7.65 (m, 2H); 7.50 (qnt, J=6 Hz, 2H); 7.34-7.18 (m, 6H);4.94 (m, 1H); 4.76 (m, 2H); 4.00 (m) and 3.81 (m) total 1H, 3.45-3.15(m, 1H); 1.61 (m, 1H); 1.43-1.15 (m, 8H); 1.08 (m, 6H); 0.79 (t, J=7 Hz,3H). ES-LCMS m/z 574 (M+H). HRMS C₃₃H₃₉N₃O₆ m/z 596.2737 (M+H)_(Cal.)596.2757 (M+Na)_(Obs).

Example 61 4-(1,2,3-Thiadiazol-4-yl)phenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

3-(1,2,3-Thiadiazol-4-yl)phenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate(4 mg, 5%) was obtained in two steps from 50.0 mg (0.12 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 24 mg (0.14 mmol) of 4-(1,2,3-thiadiazol-4-yl)phenol following theprocedure outlined in example 57 except no Dowex 50W×4(H⁺) resin wasutilized. ¹H NMR (300 MHz, DMSO-d₆) δ 9.87 (d, J=4 Hz, 1H); 9.36 (d, J=8Hz, 1H); 8.20 (d, J=7 Hz, 1H); 8.11 (s, 1H); 7.91 (t, J=8 Hz, 1H); 7.74(t, J=8 Hz, 1H); 7.52-7.35 (m, 6H); 5.15 (m, 1H); 4.93 (m, 1H); 4.19 (m)and 4.00 (m) total 1H, 3.88-3.38 (m, 3H); 1.80 (m, 1H); 1.65-1.20 (m,14H); 0.97 (t, J=7 Hz, 3H). ES-LCMS m/z 630 (M+Na).

Example 62 Phenyl3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate

To a 0° C. solution of 28 mg (0.30 mmol) of phenol in 1 mL ofdichloromethane was added a solution of 0.32 mL of phosgene (1.93 M intoluene, 0.63 mmol) in 2 mL of dichloromethane. To the resultingsolution was added dropwise 0.024 mL (0.30 mmol) of pyridine, and thereaction mixture was allowed to warm to room temperature. After 18 h, astream of nitrogen was passed through the mixture for 15 minutes, beforeit was added to a solution of 110 mg (0.27 mmol) of(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateand 0.048 mL (0.6 mmol) of pyridine in 1 mL of dichloromethane. Themixture was stirred for 4 h, and was then concentrated under reducedpressure. The residue was taken up in 4 mL of dichloromethane, and 22 mg(0.26 mmol) of sodium bicarbonate and 95 mg (0.26 mmol) of Dess-Martinperiodinane were added to the solution. The reaction mixture was stirredfor 20 minutes before being applied directly to a silica gel column.Elution with 1:9 acetone:dichloromethane afforded 80 mg (73%) of phenyl3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylateas a white foam. ¹H NMR (300 MHz, DMSO-d₆) δ 8.89 (d, J=8 Hz, 1H),7.44-7.13 (m, 11H), 4.99 (qnt, J=7 Hz, 1H), 4.88-4.72 (m, 2H), 4.03-3.75(m, 1H), 3.60-3.20 (m, 3H), 1.75-1.20 (m, 9H), 1.10 (d, J=5 Hz, 1H),0.85 (t, J=7 Hz, 3H). ES-LCMS m/z 524 (M+H) HRMS C₂₉H₃₇N₃O₆ m/z 546.2580(M+Na)⁺546.2587 (M+Na)⁺ _(Obs) Anal. calcd. for C₂₉H₃₇N₃O₆.0.1H₂O: C,66.29; H; 7.14; N. 8.00. Found: C, 65.94; H, 7.16; N, 7.91.

Example 63(3S)-1-(Anilinocarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

Example 63a Preparation of(3S)-1-(anilinocarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

To a solution of (3S)-4,4-dimethylpyrrolidinyl(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.10 g, 0.24 mmol) in anhydrous acetonitrile (2 mL) was added phenylisocyanate (0.033 g, 0.03 mL, 0.27 mmol), and the mixture was stirred atambient temperature for 1.5 h. Solvent was evaporated and the residuewas purified by chromatography (silica gel, hexanes/ethyl acetate, 2:3)to provide the title compound as a diastereomeric mixture (0.087 g,solid foam, 780%). ¹H NMR (DMSO-d₆): δ 8.09 (s, 1H), 8.01 (d, J=9 Hz,1H), 7.45 (d, J=8 Hz, 2H), 7.30-7.15 (m, 7H), 6.9-6.8 (m, 2H), 5.65 (d,J=6 Hz, 1H), 4.88 (sextuplet, J=7 Hz, 1H), 4.65 (d, J=4 Hz, 1H), 3.89(br s, 1H), 3.8-3.7 (m, 2H), 3.1-3.2 (m, 2H), 1.34 (d, J=7 Hz, 3H),1.3-1.0 (m, 13H), 0.7 (m, 3H). ES-LCMS C₂₉H₄₀N₄O₅ m/z 525.26 (M+H).

Example 63b Preparation of(3S)-1-(anilinocarbonyl)-4,4dimethylpyrrolidinyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

To a solution of (3S)-1-(anilinocarbonyl)-4,4-dimethylpyrrolidinyl(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.085 g, 0.162 mmol) in anhydrous dichloromethane (3 mL) was addedDess-Martin periodinane (0.085-g, 0.2 mmol). After 20 min at ambienttemperature, the mixture was diluted with dichloromethane and washedwith saturated sodium bicarbonate/water containing 5% sodiumthiosulfate. The organic phase was dried (sodium sulfate), concentratedand purified by chromatography (silica gel, dichloromethane/methanol,97:3) to provide the title compound as a solid foam (0.045 g, 53%). ¹HNMR (DMSO-d₆): 9.15(d, J=8 Hz, 1H), 8.1 (s, 1H), 7.65 (d, J=7 Hz, 1H),7.45 (d, J=8 Hz, 2H), 7.3-7.1 (m, 7H), 6.87 (t, J=7 Hz, 1H), 5.0-4.8 (m,1H), 4.75-4.60 (m, 2H), 3.8-3.7 (m, 1H). 3.20-3.15 (m, 3H), 1.6 (br s,1H), 1.38 (d, J=7 Hz, 3H), 1.30-0.95 (m, 11H), 0.8 (m, 3H). ES-LCMS m/z523.19 (M+H). Anal. calcd. for C₂₉H₃₈N₄₀s 0.5H₂O: C, 65.52; H, 7.39; N,10.54. Found: C, 65.40; H, 7.30; N, 10.39.

Example 64(3S)-1-[(Benzylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate)

(3S)-1-[(Benzylamino)carbonyl]-4,4-dimethylpyrrolidinyl(15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.065 g,65%) was obtained as a solid foam from (3S)-4,4-dimethylpyrrolidinyl(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.08 g, 0.19 mmol) and benzylisocyanate (0.027 g, 0.2 mmol) followed byoxidation with Dess-Martin periodinane (0.084 g, 0.2 mmol) according tothe procedures outlined in examples 63a and 63b, respectively. ¹H NMR(DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 7.61 (d, J=7 Hz, 1H), 7.30-7.15 (m,10H), 6.69 (t, J=6 Hz, 1H), 5.0-4.9 (m, 1H), 4.8-4.7 (m, 1H), 4.65-4.60(m, 1H), 4.16 (d, J=6 Hz, 2H), 3.61 (dd, J=12 Hz, 5 Hz, 1H), 3.15-3.00(m, 3H), 1.6 (br s, 1H), 1.4 (d, 3H), 1.35-1.15 (m, 5H), 0.95 (2s, 6H),0.8 (m, 3H). ES-LCMS m/z 537.2 (M+H). Anal. calcd. forC₃₀H₄₀N₄O₅.0.66H₂O: C, 65.69; H, 7.59; N, 10.21. Found: C, 65.59; H,7.44; N, 9.93.

Example 65(3S)-4,4-Dimethyl-1-{[(2-phenylethyl)amino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-{[(2-phenylethyl)amino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(0.107 g, 66% o) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.12 g, 0.29 mmol) and phenethylisocyanate (0.045 g, 0.29 mmol)followed by oxidation with Dess-Martin periodinane (0.125 g, 0.29 mmol)according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 7.61 (d, J=7 Hz,1H), 7.3-7.1 (m, 10H), 6.2-6.15 (m, 1H), 5.0-4.9 (m, 1H), 4.8-4.7 (m,1H), 4.65-4.60 (m, 1H), 3.55 (dd, J=12 Hz, 5 Hz, 1H), 3.2-2.9 (m, 5H),2.66 (t, J=8 Hz, 2H), 1.6 (br s, 1H), 1.37 (d, J=7 Hz, 3H), 1.30-1.15(m, 5H), 0.94 (2s, 6H), 0.8 (m, 3H). ES-LCMS m/z 551.19 (M+H). Anal.calcd. for C₃₁H₄₂N₄O₅.1 H₂O: C, 65.47; H, 7.80; N, 9.85. Found: C,65.28; H, 7.47; N, 9.54.

Example 66(3S)-4,4-Dimethyl-1-(3-pyridinylcarbonyl)pyrrolidinyl(1S)-7-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-(3-pyridinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(0.077 g, 51%) was obtained as a solid foam from(3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.12 g, 0.29 mmol) and nicotinoyl chloride (0.039 g, 0.22 mmol)followed by oxidation with Dess-Martin periodinane (0.125 g, 0.29 mmol)according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 9.2-9.1 (m, 1H), 8.7-8.6 (m, 2H),8.0-7.2 (m, 8H), 5.0-4.9 (m, 1H), 4.78 (br s, 1H), 4.65 (br s, 1H),4.0-3.8 (m, 1H), 3.43.15 (m, 3H), 1.6-1.5 (m, 1H), 1.40.7 (m, 17H).ES-LCMS C₂₈H₃₆N₄O₅ m/z 509.18 (M+H).

Example 67(3S)-1-{[(3,5-Dimethyl-4-isoxazolyl)amino]carbonyl}-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-{[(3,5-Dimethyl-4-isoxazolyl)amino]carbonyl}-4,4-dimethylpyrrolidinyl(15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.118 g,740%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.120 g, 0.290 mmol) and 3,5-dimethyl-4-isoxazolylisocyanate (0.041 g,0.30 mmol) followed by oxidation with Dess-Martin periodinane (0.125 g,0.290 mmol) according to the procedures outlined in examples 63a and63b, respectively. ¹H NMR (DMSO-d₆): S 9.15 (d, J=8 Hz, 1H), 7.65 (d,J=8 Hz, 1H), 7.58 (s, 1H), 7.30-7.18 (m, 5H), 5.0-4.9 (m, 1H), 4.8-4.7(m, 1H), 4.65 (br s, 1H), 3.8-3.7 (m 1H), 3.3-3.0 (m, 3H), 2.18 (s, 3H),2.01 (s, 3H), 1.6-1.5 (m, 1H), 1.38 (d, J=7 Hz, 3H), 1.3-1.1 (m, 5H),0.98 (s, 6H), 0.8 (m, 3H). ES-LCMS C₂₈H₃₉N₅O₆ m/z 542.15 (M+H).

Example 68(3S)-1-[(Cyclohexylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-[(Cyclohexylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(0.125 g, 96%) was obtained as a solid foam from(34)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.10 g, 0.24 mmol) and cyclohexylisocyanate (0.031 g, 0.24 mmol)followed by oxidation with Dess-Martin periodinane (0.111 g, 0.260 mmol)according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 7.61 (d, J=8 Hz,1H), 7.30-7.18 (m, 6H), 5.71 (d, J=8 Hz, 1H), 5.0-4.9 (m, 1H), 4.8-4.7(m, 1H), 4.58 (d, J=4 Hz, 1H), 3.54 (dd, J=12 Hz, 5 Hz, 1H), 3.17 (d,J=12 Hz, 1H), 3.10-2.95 (m, 2H), 1.7-1.5 (m, 5H), 1.37 (d, J=7 Hz, 3H),1.3-1.0 (m, 11H), 0.98 (2s, 6H), 0.8 (m, 3H). ES-LCMS m/z 529.20 (M+H).Anal. calcd. for C₂₉H₄₄N₄O₅.0.61H₂O: C, 64.54; H, 8.45; N, 10.38. Found:C, 64.44; H, 8.21; N, 9.84.

Example 69 Preparation of(3S)-1-[(4-Cyanoanilino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-[(4-Cyanoanilino)carbonyl]-4,4dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(0.070 g, 70%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.074 g, 0.18 mmol) and 4-cyanophenylisocyanate (0.027 g, 0.18 mmol)followed by oxidation with Dess-Martin periodinane (0.080 g, 0.18 mmol)according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 9.15 (d, J=8 Hz, 1H), 8.6 (s, 1H),7.8-7.6 (m, 5H), 7.30-7.15 (m, 5H), 5.0-4.9 (m, 1H), 4.8-4.6 (m, 2H),3.8-3.7 (m, 1H), 3.4-3.2 (m, 3H), 1.6 (br s, 1H), 1.38 (d, J=7 Hz, 3H),1.3-1.1 (m, 5H), 1.00, 0.99 (2s, 6H), 0.78 (m, 3H). ES-LCMS m/z 548.11(M+H). Anal. calcd. for C₃₀H₃₇N₅O₅.0.36H₂O: C, 65.02; H, 6.86; N, 12.64.Found: C, 65.03; H, 6.75; N, 12.72.

Example 70(3S)-4,4-Dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.050 g,47%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.074 g, 0.18 mmol) and α,α,α-trifluoro-p-tolylisocyanate (0.034 g,0.18 mmol) followed by oxidation with Dess-Martin periodinane (0.080 g,0.18 mmol) according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 8.51 (s, 1H),7.8-7.6 (m, 3H), 7.53 (d, J=9 Hz, 2H), 7.35-7.15 (m, 5H), 5.0-4.9 (m,1H), 4.8-4.6 (m, 2H), 3.8-3.7 (m, 1H), 3.4-3.1 (m, 3H), 1.6 (br s, 1H),1.38 (d, J=7 Hz, 3H), 1.3-1.1 (m, 5H), 1.0, 0.98 (2s, 6H), 0.78 (m, 3H).ES-LCMS m/z 591.1 (M+H). Anal. calcd. for C₃₀H₃₇F₃N₄O₅ 0.3H₂O: C, 60.45;H, 6.36; N, 9.40. Found: C, 60.46; H, 6.25; N, 9.26.

Example 71(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate

Example 71a Preparation of (3S)-4,4-dimethyl-3-pyrrolidinolhydrochloride

A solution of 6.34 g (41.7 mmol) of(3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol in 250 mL of ethanol and 50 mLof 1N hydrochloric acid was stirred under hydrogen (40 psi) for 18 h inthe presence of 300 mg of 10% Pd/C, after which the amount of 10% Pd/Cwas doubled and 2 mL of concentrated hydrochloric acid were added. Themixture was stirred for an additional 72 h under hydrogen (40 psi),before the 10%/Pd/C was filtered off over celite. The filtrate wasconcentrated and several portions of toluene were distilled from theresidue, which was then dried under high vacuum to afford 4.74 g(quantitative yield) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride.¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (m, 2H), 5.43 (br s, 1H), 3.75 (m, 1H),3.36 (m, 1H), 2.88 (m, 3H), 0.98 (s, 3H), 0.94 (s, 3H).

Example 71b Preparation of(4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamide

To 200 mg (1.3 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochlorideand 0.25 mL (1.3 mmol) of N,N-diisopropylethylamine in 4 mL ofdichloromethane was added dropwise 0.19 mL (1.3 mmol) of1-isocyanato-4-(trifluoromethyl)benzene. The reaction mixture wasstirred at room temperature for 18 h. It was then diluted with ethylacetate, and the resulting solution was washed with 1 N hydrochloricacid and brine, dried over magnesium sulfate, and concentrated underreduced pressure to afford 390 mg (quantitative yield) of(4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamide.¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H), 7.73 (d, J=9 Hz, 2H), 7.54 (d,J=9 Hz, 2H), 5.08 (s, 1H), 3.74-3.55 (m, 2H), 3.27-3.09 (m, 3H), 0.97(s, 3H), 0.95 (s, 3H). CL-LCMS m/z 303 (M+H).

Example 71 c Preparation of tert-butyl(1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate

To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]hexanoicacid (27.8 g, 120.0 mmol) in dichloromethane (150 mL) at −40° C. wasadded a solution of 1-methylpiperidine (18.4 mL, 151.5 mmol) indichloromethane (40 mL) over 20 min. Ethyl chloroformate (13.9 mL, 145.4mmol) in dichloromethane (40 mL) was then added over 30 min and thereaction mixture was stirred at −40° C. for 2.5 h. A solution ofN,O-dimethylhydroxylamine hydrochloride (14.2 g, 145.4 mmol) and1-methylpiperidine (18.4 mL, 151.5 mmol) in dichloromethane (90 mL) wasadded over 45 min, and the reaction mixture was allowed to slowly warmto ambient temperature. It was stirred for 18 h, and then washed withwater (100 mL), 1% hydrochloric acid (2×100 mL), and saturated aqueoussodium bicarbonate (100 mL). The organic layer was then dried withmagnesium sulfate and concentrated in vacuo to afford the desired titlecompound (35.0 g, 106%) as a thick oil. ¹H NMR (400 MHz, DMSO-d₆): δ6.94 (d, J=8 Hz, 1H), 4.35-4.25 (m, 1H), 3.68 (s, 3H), 3.05 (s, 3H),1.52-1.36 (m, 2H), 1.32 (s, 9H), 1.30-1.14 (m, 4H), 0.80 (t, J=6 Hz,3H).

Example 71d Preparation of tert-butyl (1S)-1-formylpentylcarbamate

To a stirred solution of bis (2-methoxyethoxy) aluminum hydride (54.0mL, 65% by weight in toluene, 180.0 mmol) in toluene (100 mL) at −20° C.was added a solution of tert-butyl(1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate (35.0 g, 120.0mmol) in toluene (100 mL) over 30 min. After 2 h at −20° C., 3M sodiumchloride (300 mL) was added dropwise, and the layers were separated. Thetoluene portion was washed with 1 N hydrochloric acid (2×100 mL), 0.1 Nsodium hydroxide (2×50 mL), and brine (50 mL), dried over magnesiumsulfate, and concentrated to 200 mL The aldehyde was used immediately insolution. An aliquot of the solution was removed and concentrated, andthe aldehyde was analyzed immediately. ¹H NMR (400 MHz, DMSO-d₆): δ 9.39(s, 1H), 7.23 (d, J=7 Hz, 1H), 3.75 (m, 1H), 1.70-1.08 (m, 6H), 1.36 (s,9H), 0.81 (t, J=6 Hz, 3H).

Example 71e Preparation of tert-butyl(15)-1-[cyano(hydroxy)methyl]pentylcarbamate

To a stirred solution of tert-butyl (1S)-1-formylpentylcarbamate intoluene was added water (50 mL), acetone cyanohydrin (16.4 mL, 180.0mmol), potassium cyanide (250 mg) and tetrabutylammonium iodide (300mg). The mixture was stirred at ambient temperature for 20 h, and thenthe layers were separated. The organic layer was washed with water (5×60mL), dried with magnesium sulfate and concentrated in vacuo to affordthe title compound (26.7 g, 92%) as a thick oil. The ¹H NMR spectrumshowed an approximately equal mixture of diastereomers. ¹H NMR (400 MHz,DMSO-d₆): δ 6.91,6.83 (2d, J=8 Hz, J=9 Hz, 1H), 6.54, 6.47 (2d, J=7 Hz,J=6 Hz, 1H), 4.44, 4.17 (2t, J=5 Hz, J=8 Hz, 1H), 3.60-3.50 (m, 1H),1.65-1.10 (m, 6H), 1.34 (s, 9H), 0.80 (t, J=6 Hz, 3H).

Example 71f Preparation of (3S)-3-amino-2-hydroxyheptanoic acidhydrochloride

A mixture of tert-butyl (1S)-1-[cyano(hydroxy)methyl]pentylcarbamate(26.7 g, 110.0 mmol) and concentrated hydrochloric acid (200 mL) wasstirred at 110° C. for 6 h and then allowed to stand at ambienttemperature for 18 h. The reaction mixture was concentrated in vacuo,toluene (200 mL) was added, and the solution was concentrated again toafford the crude title compound (25.6 g, quantitative crude yield) as awhite paste. The ¹H NMR spectrum showed this material to be anapproximately equal mixture of diastereomers containing ammoniumchloride. The material was used without further purification. ¹H NMR(400 MHz, DMSO-d₆): δ 8.25, 8.02 (2br s, 3H), 4.38,4.05 (2d, J=5 Hz, J=7Hz, 1H), 3.35-3.10 (m, 1H), 1.70-1.10(m, 6H), 0.80 (2t, J=6 Hz, 3H).

Example 71g Preparation of(3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxyheptanoic acid

To a stirred solution of (3S)-3-amino-2-hydroxyheptanoic acidhydrochloride (25.6 g crude, 110.0 mmol) in 1 N sodium hydroxide (300mL) was added a solution of di-tert-butyldicarbonate (26.4 g, 121.2mmol) in tetrahydrofuran (75 mL) over 30 min. After stirring at ambienttemperature for 20 h, the reaction mixture was diluted with ether (100mL) and the layers were separated. The aqueous layer was cooled in anice bath, acidified to pH 2 with concentrated hydrochloric acid, andextracted with dichloromethane (2×150 mL). The dichloromethane layer waswashed with brine (100 mL), dried with magnesium sulfate, andconcentrated in vacuo to afford the title compound (21.7 g, 75% over 2steps) as a thick paste. ¹H NMR (400 MHz, DMSO-d₆): δ 12.40 (broad, 1H),6.45, 6.15 (2d, J=9 Hz, J=10 Hz, 1H), 5.20, 4.98 (2br, 1H), 3.89 (2d,J=12 Hz, J=10 Hz, 1H), 3.73-3.60 (m, 1H), 1.46-1.08 (m, 6H), 1.32, 1.31(2s, 9H), 0.80 (t, J=6 Hz, 3H).

Example 71h Preparation of tert-butyl(1S)-1-[1-hydroxy-2-oxo-2-(7H-pyrazol-5-ylamino)ethyl]pentylcarbamate

To a stirred solution of(3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxyheptanoic acid (5.0 g, 19.1mmol) and 1-methylpiperidine (3.5 mL, 28.7 mmol) in dichloromethane (40mL) at −40° C. was added a solution of ethyl chloroformate (2.0 mL, 21.0mmoL) in dichloromethane (20 mL) over 20 minutes. The reaction mixturewas stirred at −40° C. for 10 min and then allowed to warm to 5° C. over30 min. N. N¹-Carbonyldiimidazole (3.4 g, 21.0 mmol) was added. After 1h, 3-aminopyrazole (4.5 g, 54.2 mmol) was added, and the reactionmixture was allowed to warm to ambient temperature. It was diluted withtoluene (60 mL), and dichloromethane was distilled off as thetemperature was slowly increased to 110° C. The mixture was stirred for20 h at that temperature. The toluene was then removed in vacuo, and theresidue was taken up in ether (150 mL). The solution was washed withwater (3×50 mL), and concentrated in vacuo. The resulting foam wasdissolved in methanol (75 mL), and 10% aqueous potassium carbonate (15mL) was added. The reaction mixture was stirred at ambient temperaturefor 48 h. The methanol was removed in vacuo and ether (150 mL) wasadded. The ether layer was washed with water (3×50 mL), dried withmagnesium sulfate, and concentrated in vacuo to afford the titlecompound (4.8 g, 77%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 12.29 (br s, 1H), 9.73, 9.50 (2br s, 1H), 7.54 (s, 1H), 6.45 (s, 1H),6.42, 6.15 (2d, J=7 Hz, J=9 Hz, 1H), 5.87, 5.57 (2br s, 1H), 3.98 (m,1H). 3.77-3.72 (m, 1H), 1.47-1.09 (m, 6H), 1.31, 1.25 (2s, 9H), 0.81,0.76 (2t, J=6 Hz, 3H); ES-LCMS m/z 327 (M+H).

Example 71i Preparation of(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate

To a 0° C. suspension of 390 mg (1.3 mmol) of(4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamidein 4 mL of dichloromethane was added 260 mg (1.3 mmol) of 4-nitrophenylchloroformate. Pyridine 0.11 mL (1.3 mmol) was added dropwise, and thereaction mixture was let warm to room temperature. The reaction mixturewas stirred for 18 h, and then concentrated to afford the carbonate asan oil. In a separate flask, 5 mL of 4M hydrochloric acid in dioxane wasadded to a suspension of 480 mg (1.3 mmol) of tert-butyl(1S)-1-[(1R)-1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate

tert-butyl(1S)-1-[(1S)-1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamatein 1 mL of dioxane. The reaction mixture was stirred for 1 h, andconcentrated under reduced pressure. The residue was dissolved in 8 mLof N,N-dimetehylformamide, and 0.69 mL (4.0 mmol) ofN,N-diisopropylethylamine was added, followed by the carbonate. Thereaction mixture was stirred for 18 h, and then diluted with ethylacetate. The resulting solution was washed with 1M aqueous sodiumhydroxide and brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography to afford 240 mg (33%) of(3S)-4,4-dimethyl-1-{[4(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate.¹H NMR (300 MHz, DMSO-d₆) δ 12.30 (m, 1H); 9.74 (m) and 9.52 (m) total1H, 8.52 (d, J=8 Hz, 1H); 7.72 (m, 2H); 7.55 (m, 3H); 7.03 (d, J=9 Hz)and 6.77 (d, J=9 Hz) total 1H, 6.45 (m, 1H); 5.94 (m) and 5.59 (m) total1H, 4.67 (m, 1H); 4.02 (m, 1H); 3.83 (m, 2H); 3.44-3.05 (m, 3H);1.60-0.75 (m, 15H). CL-LCMS m/z 555 (M+H).

Example 71j Preparation of(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-7-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate

To a solution of 220 mg (0.40 mmol) of(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(15)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate in4 mL of dichloromethane was added 210 mg (0.49 mmol) of Dess-Martinperiodinane. The reaction mixture was stirred for 30 minutes at roomtemperature and then filtered through a celite plug. The filtrate wasconcentrated, and the residue was purified by silica gel chromatographyeluting with 3:7 acetone:dichloromethane to afford 110 mg (50%) of(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate.¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (m, 1H), 10.89 (br s, 1H), 8.55 (s,1H), 7.77-7.45 (m, 6H), 6.51 (s, 1H), 4.85 (m, 1H), 4.72 (m, 1H), 3.80(m, 1H), 3.47-3.10 (m, 3H), 1.72 (m, 1H), 1.55-1.18 (m, 5H), 1.03 (m,6H), 0.83 (t, J=7 Hz, 3H). Cl-LCMS m/z 553 (M+H) HRMS C₂₅H₃₁N₆O₅F₃ m/z553.2386 (M+)_(Cal.) 553.2408 (M+H)_(Obs).

Example 72(3S)-1-[(S-Fluoro-2-methylanilino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-[(5-Fluoro-2-methylanilino)carbonyl]-4,4-dimethylpyrrolidinyl(15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.050 g,50%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.074 g, 0.18 mmol) and 5-fluoro-2-methylphenylisocyanate (0.027 g,0.18 mmol) followed by oxidation with Dess-Martin periodinane (0.080 g,0.18 mmol) according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 7.65 (d, J=7 Hz,1H), 7.51 (s, 1H), 7.4-7.2 (m, 6H), 7.13 (t, J=8 Hz, 1H), 6.77 (td, J=8Hz, 3 Hz, 1H), 4.9-5.0 (m, 1H), 4.85-4.60 (m, 2H), 3.8-3.7 (m, 1H),3.4-3.1 (m, 3H), 2.12 (s, 3H), 1.6 (br s, 1H), 1.38 (d, J=7 Hz, 3H),1.3-1.1 (m, 5H), 1.00, 0.99 (2s, 6H), 0.78 (m, 3H). ES-LCMS m/z 555.2(M+H). Anal. calcd. for C₃₀H₃₉FN₄O₅.0.35H₂O: C, 64.23; H, 7.13; N, 9.99.Found: C, 64.24; H, 7.06; N, 10.12.

Example 73(3S)-4,4-Dimethyl-1-(4-morpholinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

To a solution of (3S)-4,4-dimethylpyrrolidinyl(15)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.074 g, 0.18 mmol) and triethylamine (0.036 g, 0.05 mL, 0.36 mmol) inanhydrous dichloromethane (2.5 mL) at 0° C. was added morpholine4-carbonyl chloride (0.027 g, 0.021 mL, 0.18 mmol), and the mixture wasstirred at 0° C. for 1 h. The mixture was diluted with dichloromethaneand washed with saturated sodium bicarbonate/water, dried (sodiumsulfate), and concentrated. The residue was dissolved in dichloromethane(3 mL) and Dess-Martin periodinane (0.076 g, 0.18 mmol) was added. After1 h at ambient temperature, dichloromethane was added and the mixturewas stirred with saturated sodium bicarbonate/water containing 5% sodiumthiosulfate. The organic phase was dried (sodium sulfate), concentratedand purified by chromatography (silica gel, hexanes/ethyl acetate, 2:3)to provide the title compound as a solid foam (0.061 g, 60%). ¹H NMR(DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 7.61 (d, J=7 Hz, 1H), 7.35-7.15 (m,5H), 5.0-4.9 (m, 1H), 4.8-4.7 (m, 1H), 4.61 (d, J=4 Hz, 1H), 3.8 (dd,J=12 Hz, 5 Hz, 1H), 3.6-3.5 (m, 4H), 3.2-3.0 (m, 7H), 1.6 (br s, 1H),1.37 (d, J=7 Hz, 3H), 1.3-1.1 (m, 5H), 0.94, 0.90 (2s, 6H), 0.78 (m,3H). ES-LCMS m/z 517.2 (M+H). Anal. calcd. for C₂₇H₄₀N₄O₆.0.19H₂O: C,62.36; H, 7.83; N, 10.77. Found: C, 62.35; H, 7.77; N, 10.55.

Example 74(3S)-4,4-Dimethyl-1-(1-pyrrolidinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-(1-pyrrolidinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(0.057 g, 66%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.070 g, 0.17 mmol) and pyrrolidine carbonyl chloride (0.023 g, 0.17mmol) followed by oxidation with Dess-Martin periodinane (0.080 g, 0.18mmol) according to the procedure described in example 73. ¹H NMR(DMSO-d₆): δ 9.14 (d, J=8 Hz, 1H), 7.6 (d, J=7 Hz, 1H), 7.35-7.15 (m,5H), 5.0-4.9 (m, 1H), 4.85-4.75 (m, 1H), 4.6 (d, J=4 Hz, 1H), 3.73 (dd,J=12, 5 Hz, 1H), 3.4-3.0 (m, 7H), 1.8-1.6 (m, 4H), 1.55 (br s, 1H), 1.37(d, J=7 Hz, 3H), 1.35-1.15 (m, 5H), 0.94, 0.92 (2s, 6H), 0.8 (m, 3H).ES-LCMS C₂₇H₄₀N₄O₅ m/z 501.21 (M+H).

Example 75(3S)-1-[(Benzoylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-[(Benzoylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.060 g,63%) was obtained as a solid foam from(3S)-4,4dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.071 g, 0.17 mmol) and benzoylisocyanate (90% pure, 0.029 g, 0.17mmol) followed by oxidation with Dess-Martin periodinane (0.074 g, 0.17mmol) according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 10.17, 10.12 (2s, 1H), 9.13 (br s,1H), 7.8 (br s, 2H), 7.7 (br s, 1H), 7.60-7.55 (m, 1H), 7.5-7.4 (m, 2H),7.3-7.2 (m, 4H), 7.19-7.14 (m, 1H), 5.0-4.9 (m, 1H), 4.8-4.6 (m, 2H),3.9-3.8 (m, 1H), 3.43.2 (m, 3H), 1.6 (br s, 1H), 1.4-1.1 (m, 8H), 1.0,0.97 (2s, 6H), 0.8-0.7 (m, 3H). ES-LCMS m/z 551.11 (M+H). Anal. calcd.for C₃₀H₃₈N₄O₆.0.23H₂O: C, 64.95; H, 6.99; N, 10.10. Found: C, 64.94; H,6.96; N, 9.95.

Example 76(3S)-4,4-Dimethyl-1-({[(4-methylphenyl)sulfonyl]amino}carbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-({[(4methylphenyl)sulfonyl]amino}carbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.056 g,54%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.071 g, 0.17 mmol) and p-toluenesulfonylisocyanate (0.034 g, 0.17mmol) followed by oxidation with Dess-Martin periodinane (0.074 g, 0.17mmol) according to the procedures outlined in examples 63a and 63b,respectively. ¹H NMR (DMSO-d₆): δ 10.63 (s, 1H), 9.18 (br s, 1H), 7.74(d, J=8 Hz, 2H), 7.62 (br s, 1H), 7.34 (d, J=8 Hz, 2H), 7.3-7.2 (m, 5H),5.0-4.9 (m, 1H), 4.8-4.5 (m, 2H), 3.8-3.7 (m, 1H), 3.2-2.9 (m, 3H), 2.34(s, 3H), 1.6-1.5 (m, 1H), 1.37 (d, J=7 Hz, 3H), 1.3-1.1 (m, 5H), 0.92(s, 6H), 0.8-0.7 (m, 3H). ES-LCMS C₃₀H₄₀N₄O₇S m/z 601.09 (M+H).

Example 77 (3S)-4,4-Dimethyl-1-(phenylsulfonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyl-1-(phenylsulfonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate(0.087 g, 81%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.080 g, 0.20 mmol) and benzenesulfonyl chloride (0.037 g, 0.21 mmol)followed by oxidation with Dess-Martin periodinane (0.089 g, 0.21 mmol)according to the procedure described in example 73. ¹H NMR (DMSO-d₆): δ9.12 (d, J=8 Hz, 1H), 7.8-7.5 (m, 6H), 7.3-7.1 (m, 5H), 5.0-4.9 (m, 1H),4.7-4.6 (m, 1H), 4.5 (d, J=3 Hz, 1H), 3.5 (dd, J=12 Hz, 5 Hz, 1H), 3.12(d, J=10 Hz, 1H), 3.05 (d, J=10 Hz, 1H), 3.0 (d, J=10 Hz, 1H), 1.6 (brs, 1H), 1.36 (d J=7 Hz, 3H), 1.40-1.15 (m, 5H), 0.83 (s, 3H), 0.77 (m,3H), 0.62 (s, 3H). ES-LCMS m/z 544.11 (M+H). Anal. calcd. forC₂₈H₃₇N₃O₆S: C, 61.86; H, 6.86; N. 7.73. Found: C, 61.58; H, 6.87; N,7.62.

Example 78(3S)-1-(Benzyl]sulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-(Benzylsulfonyl)-4,4-dimethylpyrrolidinyl(15)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (0.053 g,55%) was obtained as a solid foam from(3S)-4,4-dimethylpyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate(0.070 g, 0.17 mmol) and α-toluenesulfonyl chloride (0.035 g, 0.18 mmol)followed by oxidation with Dess-Martin periodinane (0.068 g. 0.16 mmol)according to the procedure described in example 73. ¹H NMR (DMSO-d₆): δ9.14 (d, J=8 Hz, 1H), 7.67 (d, J=7 Hz, 1H), 7.4-7.1 (m, 10H), 5.0-4.9(m, 1H), 4.8-4.7 (m, 1H), 4.58(d, J=3 Hz, 1H), 4.42(d, J=13 Hz, 1H),4.34(d, J=13 Hz, 1H), 3.6 (dd, J=12 Hz, 5 Hz, 1H), 3.14 (d, J=11 Hz,1H), 3.05 (d, J=9 Hz, 1H), 3.02 (d, J=9 Hz, 1H), 1.6 (br s, 1H), 1.37(d, J=7 Hz, 3H), 1.3-1.1 (m, 5H), 0.95 (s, 6H), 0.78 (m, 3H). ES-LCMSm/z 558.13 (M+H). Anal, calcd. for C₂₉H₃₉N₃O₆S: C, 62.46; H, 7.05; N,7.53. Found: C, 62.25; H, 7.04; N, 7.37.

Example 79(3S)-1-(1,3-Benzodioxol-5-ylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-(1,3-Benzodioxol-5-ylsulfonyl)-4,4dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (66 mg, 570%) was obtained as a white foam in two stepsfrom (3S)-4,4dimethylpyrrolidinyl2-hydroxy-3-oxo-3-{[(1R)-1-phenylethyl]amino}propylcarbamate (80 mg,0.20 mmol) and 1,3-benzodioxole-5-sulfonyl chloride (46 mg, 0.21 mmol)following the procedure outlined in example 73. ¹H NMR (400 MHz,DMSO-d₆): δ 9.12 (d, J=8 Hz, 1H), 7.54 (d, J=7 Hz, 1H), 7.31-7.06 (m,8H), 6.13 (d, 2H), 4.94-4.89 (m, 1H), 4.69-4.64 (m, 1H), 4.51-4.50 (m,1H), 3.53-3.46 (m, 1H), 3.11-2.96 (m, 3H), 1.70-1.11 (m, 6H), 1.36 (d,J=7 Hz, 3H), 0.85 (s, 3H), 0.76 (t, J=7 Hz, 3H), 0.67 (s, 3H). ES-LCMSC₂₉H₃₇N₃O₈S₁ m/z 588 (M+H).

Example 80(3S)-7-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-1-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-4,4dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate (78 mg,66%) was obtained as a white foam in two steps from(3S)-4,4-dimethylpyrrolidinyl2-hydroxy-3-oxo-3-{[(1R)-1-phenylethyl]amino}propylcarbamate (80.0 mg,0.20 mmol) and 2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (49 mg,0.21 mmol) following the procedure outlined in example 73. ¹H NMR (400MHz, DMSO-d₆): δ 9.12 (d, J=8 Hz, 1H), 7.54 (d, J=7 Hz, 1H), 7.29-7.01(m, 8H), 4.93-4.89 (m, 1H), 4.69-4.65 (m, 1H), 4.51-4.50 (m, 1H),4.28-4.26 (m, 4H), 3.51-3.47 (m, 1H), 3.10-2.96 (m, 3H), 1.70-1.13 (m,6H), 1.36 (d, J=7 Hz, 3H), 0.84 (s, 3H), 0.76 (t, J=7 Hz, 3H), 0.67 (s,3H). ES-LCMS C₃₀H₃₉N₃O₈S₁ m/z 602 (M+H).

Example 81 (3S)-1-(1,3-Benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(7S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate

Example 81a Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol

To a slurry of 600 mg (4 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinolhydrochloride and 670 mg (4 mmol) of 2-chlorobenzthiazole was added asolution of 1.0 g (12 mmol) of sodium bicarbonate in water. The reactionmixture was stirred at 80° C. overnight, diluted with water, andextracted with ethyl acetate. The extract was dried over magnesiumsulfate and concentrated under reduced pressure to afford 950 mg (96%)of (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol. ¹H NMR(300 MHz, DMSO-d₆) δ 7.72 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.23(t, J=7 Hz, 1H), 7.00 (t, J=7 Hz, 1H), 5.23 (d, J=5 Hz, 1H), 3.84 (m,1H), 3.77 (m, 1H), 3.38-3.21 (m, 3H) 1.02 (s 3H), 1.00 (s, 3H). Cl-LCMSm/z 249 (M+H).

Example 81 b Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate

(3S)-1-(1,3-Benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate(95 mg, 20%) was obtained from(3S)-1-(1,3-benzothiazol-2-yl)-4,4dimethyl-3-pyrrolidinol (230 mg, 0.93mmol) following the procedure outlined in example 71i. ¹H NMR (400 MHz,DMSO-d₆) δ 12.33 (m, 1H); 9.74 (m) and 9.55 (m) total 1 H, 7.75 (d, J=7Hz, 1H); 7.58 (s, 1H); 7.44 (m, 1H); 7.25 (t, J=8 Hz, 1H); 7.04 (t, J=8Hz, 1H); 6.47 (m, 1H); 5.94 (m) and 5.59 (m) total 1H, 4.80 (m, 1H);4.06-3.85 (m, 4H); 3.40 (m overlapping water peak 3H) 1.55-0.75 (m,15H). Cl-LCMS m/z 501 (M+H).

Example 81c Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(15)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate

(3S)-1-(1,3-Benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate(60 mg, 67%) was obtained from(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate(90 mg, 0.18 mmol) following the procedure outlined in example 71j. ¹HNMR (300 MHz, DMSO-d₆) δ 12.48 (m, 1H), 10.89 (s, 1H), 7.76 (t, J=7 Hz,2H), 7.65 (s, 1H), 7.44 (d, J=8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 7.03 (t,J=8 Hz, 1H), 6.51 (s, 1H), 4.85 (m, 2H), 3.96 (m, 1H), 3.50-3.20 (m,3H), 1.71 (m, 1H), 1.53-1.20 (m, 5H), 1.09 (s, 3H), 1.07 (s, 3H), 0.83(t, J=7 Hz, 3H). ES-LCMS m/z 499 (M+H) HRMS C₂₄H₃₀N₆O₄S₁ m/z 499.2128(M+)_(Cal.) 499.2141 (M+H)_(Obs).

Example 82(3S)-4,4-Dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]pyrrolidinyl-(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate

Example 82a Preparation of(3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-pyrrolidinol

To 3 mL of 48% aqueous HBr was added 1.0 g (5.9 mmol) of5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine with stirring. The mixturewas cooled in a salt ice-water bath, and 2.27 mL (44 mmol) of brominewas added slowly dropwise. The salt ice-water bath was replaced with anice-water bath and a solution of 1.05 g (15 mmol) of sodium nitrite in1.5 mL of water was added slowly dropwise. The reaction mixture wasstirred for 1 h and then let warm to room temperature. The mixture wasneutralized with 5M aqueous sodium hydroxide, and the resultingprecipitate was filtered off. The filtrate was extracted withchloroform, and the extract was dried over magnesium sulfate beforebeing concentrated to afford 750 mg (54%) of2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole, 330 mg (1.4 mmol) ofwhich was added to a solution of 240 mg (1.6 mmol) of(3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 0.73 mL (4.2 mmol) ofN,N-diisopropylethylamine in 5 mL of isopropanol. The reaction mixturewas heated at reflux for 2 h, and then concentrated. The residue waspurified by silica gel chromatography eluting with 0.3:9.7 methanoldichloromethane to afford 328 mg (88%) of(3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-pyrrolidinol.¹H NMR (300 MHz, DMSO-d₆) δ 5.31 (d, J=5 Hz, 1H), 3.89-3.76 (m, 2H),3.40-3.22 (m, 3H), 1.02 (s, 3H), 1.00 (s, 3H). Cl-LCMS m/z 268 (M+H).

Example 82b Preparation of(3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]pyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate

(3S)-4,4-Dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]pyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate(30 mg, 21%) was obtained from(3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-3-pyrrolidinol(330 mg, 1.2 mmol) following the procedure outlined in example 71i.Cl-LCMS m/z 520 (M+H).

Example 82c Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate

(3S)-1-(1,3-Benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate(25 mg, 84%) was obtained from(3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]pyrrolidinyl(1S)-1-[1-hydroxy-2-oxo-2-(1H-pyrazol-5-ylamino)ethyl]pentylcarbamate(30 mg, 0.058 mmol) following the procedure outlined in example 71j. ¹HNMR (300 MHz, DMSO-d₆, Temp=100° C.) δ 10.41 (m, 1H), 7.57 (s, 1H), 7.42(m, 1H), 6.46 (m, 1H), 4.87 (m, 2H), 3.99 (m, 1H), 3.51-3.38 (m, 3H),1.81 (m, 1H), 1.56 (m, 1H), 1.32 (m, 4H), 1.10 (m, 6H), 0.85 (m, 3H).Cl-LCMS m/z 518 (M+H) HRMS C₂₀H₂₆N₇O₄S₁F₃ m/z 518.1797 (M+H)_(Cal.)518.1805 (M+H)_(Obs).

Example 83 (3S)-4,4-Dimethyltetrahydro-3-furanyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl) pentylcarbamate

Example 83a Preparation of2-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylpropyl4-methylbenzenesulfonate

To a solution of 670 mg (5.0 mmol) of(2S)-3,3-dimethyl-1,2,4-butanetriol in 10 mL of tetrahydrofuran and 5 mLof 3-pentanone was added 40 mg of p-toluensulfonic acid, and thereaction mixture was heated at 70° C. overnight. It was concentrated andthe residue was purified by silica gel chromatography eluting with 3:7ether:hexanes to afford 880 mg of a liquid. The liquid was dissolved in5 mL of pyridine and cooled to 0° C. before 1.6 g (8.7 mmol) ofp-toluenesulfonyl chloride was added. The reaction mixture was allowedto warm to room temperature, and was stirred for 5 hours before beingleft to stand at 4° C. for 72 h. It was then diluted with water, andextracted with ether. The extracts were washed with saturated sodiumbicarbonate and brine, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 2.5:7.5ether:dichloromethane to afford 930 mg (52%) of2-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylpropyl4-methylbenzenesulfonate. ¹H NMR (300 MHz, CDCl₃) δ 7.61 (dd, J=13 Hz,J=8 Hz, 4H), 3.81-3.97 (m, 4H), 3.65 (t, J=7 Hz, 1H), 2.49 (s, 3H),1.65-1.53 (m, 4H), 0.93 (d, J=7 Hz, 6H), 0.87 (dt, J=7 Hz, J=2 Hz, 6H).Cl-GCMS m/z 357 (M+H).

Example 83b Preparation of (3S)-tetrahydro-3-furanol

A solution of 540 mg (1.5 mmol) of2-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-2-methylpropyl4-methylbenzenesulfonate in 2 mL of 1N hydrochloric acid and 4 mL oftetrahydrofuran was stirred at room temperature for 5 d. Solid sodiumchloride was added to the reaction mixture, which was then extractedwith ethyl acetate. The combined ethyl acetate layers were dried overmagnesium sulfate and concentrated. The residue was purified by silicagel chromatography eluting with 1:1 ethyl acetate:hexanes to afford 120mg (69%) of (3S)-tetrahydro-3-furanol. ¹H NMR (400 MHz, DMSO-d₆) δ 4.83(m, 1H), 3.89 (dd, J=9 Hz, J=5 Hz, 1H), 3.62 (dd, J=5 Hz, J=3 Hz), 3.38(dd, J=9 Hz, J=3 Hz, 1H), 3.36 (1/2Abq, J=8 Hz, 1H), 3.28 (1/2Abq, J=8Hz, 1H), 0.88 (s, 3H), 0.85 (s, 3H).

Example 83c Preparation of (3S)-4,4-dimethyltetrahydro-3-furanyl1-(1hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

(3S)-4,4-dimethyltetrahydro-3-furanyl1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatewas prepared in 47% yield from 3-(3S)-tetrahydro-3-furanol and3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide following theprocedure outlined in example 3c. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.31(m, 5H), 6.97 (d, J=7 Hz, 1H), 5.40 (d, J=9 Hz, 1H), 5.15 (qnt, J=14 Hz,1H), 4.74 (d, J=3 Hz, 1H), 4.24-4.17 (m, 2H), 3.87 (m, 1H), 3.73 (dd,J=11 Hz, J=2 Hz, 1H), 3.55 (s, 2H), 1.64 (m, 5H), 1.53 (d, J=7 Hz, 3H),1.33 (m, 4H), 1.09 (s, 3H), 0.98-0.89 (m, 3H). ES-LCMS m/z 407 (M+H).

Example 83d Preparation of (3S)-4,4-dimethyltetrahydro-3-furanyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate

(3S)-4,4-Dimethyltetrahydro-3-furanyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared in53% yield from (3S)-4,4-dimethyltetrahydro-3-furanyl1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamatefollowing the procedure outlined in example 3d. ¹H NMR (300 MHz,DMSO-d₆) δ 9.20 (m, 1H), 7.68 (d, J=7 Hz, 1H), 7.39-7.21 (m, 5H), 4.99(qnt, J=7 Hz, 1H), 4.78 (m, 1H), 4.68 (m, 1H), 4.10 (m, 1H), 3.59 (m,1H), 1.38 (m, 2H), 1.80-1.18 (m, 9H), 1.040.79 (m, 9H). ES-LCMS m/z 405(M.

Biological Data

The compounds of the present invention elicit important and measurablepharmacological responses. Each of the compounds exemplified in theExamples section bind with high affinity (IC₅₀<10 μM) to the cathepsin Kenzyme, as described by the cathepsin K assay recited below.

All assays for cathepsin K were carried out with human and ratrecombinant enzyme. Assays for cathepsins S

V were also carried out with human recombinant enzyme. Assays for humancathepsins B, H, and L were carried out with enzyme, purchased fromAthens Research and Technology, Inc., prepared from human liver tissue.Standard assay conditions for the determination of kinetic constantsused a fluorogenic peptide substrate, typically(5S,8S)-β-amino-5-benzyl-13-imino-3-methylene-N-(4-methyl-2-oxo-2H-chromen-7-yl)-6-oxo-1-phenyl-2-oxa-4,7,12triazatridecane-8-carboxamide(Cbz-Phe-Arg-AMC), and were determined in 100 mM sodium acetate at pH5.5 containing 10 mM dithiothreitol and 120 mM sodium chloride. A stocksubstrate solution of Cbz-Phe-Arg-AMC was prepared at a concentration of50 mM in dimethyl sulfoxide. This substrate was diluted into the assayfor a final substrate concentration of 10 μM in the rat cathepsin K,human cathepsin K, and human cathepsin B assays; a final substrateconcentration of 5 μM in the human cathepsin L assay; and a finalsubstrate concentration of 2 μM in the human cathepsin V assay.

A stock substrate solution of benzyl(1S)-1-{[((1S)-1-{[((1S)-4-{[amino(imino)methyl]amino}-1-{[(4-methyl-2-oxo-2H-chromen-7-yl)amino]carbonyl}-butyl)amino]carbonyl}-2-methylpropyl)amino]carbonyl}-2-methylpropylcarbamate(Cbz-Val-Val-Arg-AMC) was prepared at a concentration of 10 mM indimethyl sulfoxide. This substrate was diluted into the assay for afinal substrate concentration of 10 μM in the human cathepsin S assay.

A stock substrate solution of(2S)-2-amino-5-{[amino(imino)methyl]amino}-N-(2-naphthyl)pentanamidehydrochloride (L-Arg-β-naphthalamide-HCl) was prepared at aconcentration of 10 mM in dimethyl sulfoxide. This substrate was dilutedinto the assay for a final substrate concentration of 50 μM in thecathepsin H assay.

All assays contained 10% dimethyl sulfoxide. Independent experimentsfound that this level of dimethyl sulfoxide had no effect on kineticenzymatic constants. All assays were conducted at 30° C. Productfluorescence (excitation at 360 nm; emission at 440 nm, (exceptcathepsin H which used excitation at 340 nm; emission at 420 nm)) wasmonitored with a PerSeptive Biosystems Cytofluor II fluorescence platereader. Product progress curves were generated over 2.3 h monitoring theformation of 7-amino-4-methylcoumarin product (or β-naphthalamide forcathepsin H).

Human and rat Cathepsin K:

Scale-Up and Fermentation: The method of O'Reilly et al. (1994) was usedfor baculovirus expression with the following details. Two liters ofSpodoptera frugiperda (Sf-9) cells (ATCC) were grown in Grace'sSupplemented medium (Life Technologies) supplemented with 2 g/L glucose,10% fetal bovine serum (HyClone) and 0.1% pluronic F-68 (LifeTechnologies). Cells were grown in a 6 L shake flask at 150 RPM at 28°C. for 24 h to a density of 106 cells/mL, and then infected at amultiplicity of infection (MOI) of 0.1. The cells continued to grow for72 h post-infection, before the virus was harvested by centrifugation at1400×g for 30 min. Virus was titered as described (Summers and Smith,1987).

One and one-half liters of Trichoplusia ni (T. ni) High Five (TM) cells[JRH Biosciences, Woodland, Calif. (adapted to suspension and serum-freemedium)] grown in Excell 405 (TM) medium (JRH Biosciences) with 50 ug/mLgentamicin (Life Technologies) were added to a 15 L stirred tank reactor(Quark Enterprises, Inc) at a density of ˜0.5×106 cells/mL The cellswere grown for 24 h at 28° C., 50 RPM, and 50% dissolved oxygen. Cellswere then infected at a density of ˜106 cells/mL with an MOI of 1 andgrown for 48 h post-infection. Media were separated from cells at a rateof 1 L/min using the Centritech 100 (TM) continuous-flow centrifuge(DuPont) operating at 200×g.

Protein Purification: Media (human and rat) were filtered through aWhatman 3 filter, and then loaded onto a 25 mL Poros HS II (26 mm×47 mm)cation exchange column equilibrated in 25 mM sodium acetate at pH 5.5(equilibration buffer). The column was washed until the absorbancereached the baseline value, and then the protein was eluted with alinear gradient from 0-2 M sodium chloride in the equilibration buffer.Column fractions were analyzed by SDS-PAGE, N-terminal sequencing, andmass spectrometry. Fractions containing the proform of cathepsin K werepooled and frozen at −80° C. The proform was concentrated in an AmiconCentriprep 10 and fractionated with a Superdex 75 column (26 mm×600 mm,Pharmacia) equilibrated in 400 mM sodium chloride, 25 mM sodium acetateat pH 5.5.

Cathepsin K Activation: The proform of cathepsin K was converted tomature cathepsin K by brief exposure to pH 4 in the presence of 5 mML-cysteine. Typically, 5 mM L-cysteine was added to 10 mL ofapproximately 1 mg/mL procathepsin K. One mL of this solution wasdiluted ten-fold into 450 mM sodium acetate at pH 4.0 containing 5 mML-cysteine. This solution was reacted at 23° C. for 2 min beforeneutralization with 2 mL 1.8 M sodium acetate at pH 6.0. The neutralizedsample was added to the remaining 9 mL of procathepsin K. The mixturewas incubated at 4° C. for 2-3 days. The activated cathepsin K waschromatographed on a Poros HS II column as described above.

Inhibition Studies

Potential inhibitors were evaluated using the progress curve method.Assays were carried out in the presence of variable concentrations oftest compound. Reactions were initiated by addition of bufferedsolutions of inhibitor and substrate to enzyme. Data analysis wasconducted according to one of two procedures depending on the appearanceof the progress curves in the presence of inhibitors. For thosecompounds whose progress curves were linear, the enzymatic activity(RATE) was plotted against the concentration of test compound, includinginhibitor concentration of zero ([I]=0), and the IC₅₀ determined from afit of equation 1 to the data,RATE=V _(max)/(1+([1]/IC50))  (1)where V_(max) is the best fit estimate of the maximal enzymaticactivity. K_(i) values were calculated from IC₅₀ values using equation 2assuming a competitive model. $\begin{matrix}{K_{i} = {{IC}_{50}*\lbrack {1 - \frac{S}{( {S + K_{m}} )}} \rbrack}} & (2)\end{matrix}$

For those compounds whose progress curves showed downward curvaturecharacteristic of time-dependent inhibition, the data from individualsets was analyzed using the computer program DynaFit (Kuzmic, P. Anal.Biochem. 1996, 237. 260-273) to give Ki values according to thefollowing kinetic mechanism: TABLE 1 = Inhibition of Cathepsin K (IC ⁵⁰in nM) Cathepsin Inhibitory Activity Example h Cat K IC₅₀ 1 +++ 2 +++ 3+++ 4 ++ 5 ++ 6 +++ 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 +++ 12 +++ 13 ++ 14 +++15 +++ 16 +++ 17 +++ 18 +++ 19 ++ 20 +++ 21 +++ 22 +++ 23 ++ 24 ++ 25 ++26 ++ 27 ++ 28 ++ 29 ++ 30 ++ 31 ++ 32 ++ 33 ++ 34 ++ 35 +++ 36 +++ 37++ 38 ++ 39 ++ 40 +++ 41 +++ 42 ++ 43 ++ 44 ++ 45 ++ 46 +++ 47 ++ 48 +49 ++ 50 ++ 51 +++ 52 ++ 53 +++ 54 ++ 55 ++ 56 ++ 57 +++ 58 ++ 59 ++ 60++ 61 ++ 62 ++ 63 +++ 64 +++ 65 +++ 66 ++ 67 ++ 68 ++ 69 ++ 70 +++ 71++++ 72 +++ 73 ++ 74 ++ 75 ++ 76 + 77 +++ 78 ++ 79 ++ 80 ++ 81 ++++ 82++++ 83 +++ Inhibitors (1,000-100 nM)++ Potent inhibitors (100-10 nM)+++ More potent inhibitors (10-1 nM)++++ Most potent inhibitors (1-0.1 nM)

TABLE 2 Inhibition of Cathepsins B, H, K, L, S, and V(IC₅₀ in nM) Ex-am- h Cat B h Cat H h Cat K r Cat K h Cat L h Cat S h Cat V ple IC₅₀IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ 71 + + ++++ ++ + +++ ++ 82 + + ++++ ++ +++ +++ Inhibitors (1,000-100 nM)++ Potent inhibitors (100-10 nM)+++ More potent inhibitors (10-1 nM)++++ Most potent inhibitors (1-0.1 nM)

1. A compound of Formula (I):

or a salt, solvate, or physiologically functional derivative thereofwherein A is the group defined by (Q⁴)_(p)-(Q³)_(n)-(Q²)_(m)-(Q¹)-,wherein Q¹ is heterocyclyl or heterocyclylene, Q² is OC(O), C(O),N(H)C(O), C(O)N(H)C(O), S(O)₂N(H)C(O), S(O)₂, or N(H)S(O)₂ and m is 0 or1, Q³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, aralkyl,aralkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, orheterocyclylene, and n is 0 or 1, and Q⁴ is C₁-C₆ alkyl, C₁-C₆haloalkyl, aryl, aryloxy, heteroaryl, halo, or cyano, and p is 0, 1, or2; D is O or S; R is hydrogen or —N(R¹)—R²—R³; R¹ is hydrogen or C₁-C₆alkyl; R² is C(O), C(O)O, C(O)N(H), SO₂, or SO₂N(H); R³ is hydrogen orC₁-C₆ alkyl; Z is the group defined by —(X)_(m)—(X¹), wherein X isC(R′)(R″), wherein R′ is hydrogen or C₁-C₆ alkyl, R″ is hydrogen orC₁-C₆ alkyl, and m is 0, 1, or 2; and X¹ is aryl, heteroaryl, orheterocyclyl.
 2. A compound of Formula (II):

or a salt, solvate, or physiologically functional derivative thereofwherein A′ is the group defined by (Q⁴)_(p)-(Q³)_(n)-(Q²)_(m), whereinQ² is OC(O), C(O), N(H)C(O), C(O)N(H)C(O), S(O)₂N(H)C(O), S(O)₂, orN(H)S(O)₂ and m is 0 or 1, Q³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇cycloalkyl, aralkyl, aralkylene, aryl, arylene, heteroaryl,heteroarylene, heterocyclyl, or heterocyclylene, and n is 0 or 1, and Q⁴is C₁-C₆ alkyl, C₁-C₆ haloalkyl, aryl, aryloxy, heteroaryl, halo, orcyano, and p is 0, 1, or 2; R_(a) is hydrogen or oxo; R^(b) is hydrogenor C₁-C₆ alkyl; R^(c) is hydrogen or C₁-C₆ alkyl; R is hydrogen or—N(R¹)—R²—R³; R¹ is hydrogen or C₁-C₆ alkyl; R² is C(O), C(O)O,C(O)N(H), SO₂, or SO₂N(H); R³ is hydrogen or C₁-C₆ alkyl; Z is the groupdefined by —(X)_(m)—(X¹), wherein X is C(R′)(R″), wherein R′ is hydrogenor C₁-C₆ alkyl, R″ is hydrogen or C₁-C₆ alkyl, and m is 0, 1, or 2; andX¹ is aryl, heteroaryl, or heterocyclyl.
 3. A compound as claimed inclaim 1, wherein m is 0, n is 0, and p is 0 and A is (Q¹)-.
 4. Acompound as claimed in claim 1, wherein n is 0, p is 0 and A is(Q²)_(m)-(Q¹)-.
 5. A compound as claimed in claim 1, wherein p is 0 andA is (Q³)_(n)-(Q²)_(m)-(Q¹)-.
 6. A compound as claimed in claim 1,wherein m is 0, n is 1, p is 0, 1, or 2, and A is (Q⁴)_(p)-(Q³)-(Q¹)-.7. A compound as claimed in claim 1, wherein Q¹ is heterocyclyl.
 8. Acompound as claimed in claim 1, wherein Q¹ is heterocyclylene.
 9. Acompound as claimed in claim 1, wherein Q¹ is selected from the group

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.
 10. A compound as claimed in claim 1, wherein Q¹ is selected fromthe group

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.
 11. A compound as claimed in claim 1, wherein Q¹ is

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.
 12. A compound as claimed in claim 1, wherein Q¹ is selected fromthe group

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.
 13. A compound as claimed in claim 1, wherein Q¹ is selected fromthe group

wherein R^(b) is hydrogen or C₁-C₆ alkyl and R^(c) is hydrogen or C₁-C₆alkyl.
 14. A compound as claimed in claim 1, wherein m is 1 and Q² isOC(O), C(O), N(H)C(O), S(O)₂, or N(H)S(O)₂.
 15. A compound as claimed inclaim 1, wherein m is 1 and Q² is OC(O) or C(O).
 16. A compound asclaimed in claim 1, wherein m is 1 and Q² is C(O).
 17. A compound asclaimed in claim 1, wherein m is 1 and Q² is N(H)C(O).
 18. A compound asclaimed in claim 1, wherein m is 1 and Q² is S(O)₂.
 19. A compound asclaimed in claim 1, wherein n is 1 and Q³ is aryl or arylene, heteroarylor heterarylene, heterocyclyl or heterocyclylene, or aralkyl oraralkylene.
 20. A compound as claimed in claim 1, wherein, Q³ is aryl orarylene.
 21. A compound as claimed in claim 1, wherein Q³ is selectedfrom the group


22. A compound as claimed in claim 1, wherein Q³ is


23. A compound as claimed in claim 1, wherein Q³ is aralkyl oraralkylene.
 24. A compound as claimed in claim 1, wherein Q³ is selectedfrom the group


25. A compound as claimed in claim 1, wherein Q³ is selected from thegroup


26. A compound as claimed in claim 2, wherein Q³ is selected from thegroup


27. A compound as claimed in claim 1, wherein Q³ is heteroaryl orheteroarylene.
 28. A compound as claimed in claim 1, wherein Q³ isselected from the group


29. A compound as claimed in claim 1, wherein Q³ is heterocyclyl orheterocyclylene.
 30. A compound as claimed in claim 1, wherein Q³ isselected from the group


31. A compound as claimed in claim 1, wherein Q⁴ is methyl, tert-butyl,—CF₃, phenyl, phenoxy, isoxazolyl, thiadiazolyl, thienyl, pyrazinyl,fluoro, chloro, cyano, and p is 1 or
 2. 32. A compound as claimed inclaim 1, wherein Q⁴ is methyl, tert-butyl, —CF₃, phenyl, phenoxy, andfluoro and p is 1 or
 2. 33. A compound as claimed in claim 1, wherein Q⁴is methyl, and p is
 1. 34. A compound as claimed in claim 1, wherein Dis O.
 35. A compound as claimed in claim 1, wherein R is hydrogen.
 36. Acompound as recited in claim 1, wherein m is 0 and Z is —(X¹).
 37. Acompound as claimed in claim 1, wherein X is CHR″, R″ is hydrogen and mis 0, 1, or 2,
 38. A compound as claimed in claim 1, wherein X is CHR″,R″ is —CH₃ and m is
 1. 39. A compound as claimed in claim 1, wherein X¹is aryl.
 40. A compound as claimed in claim 1, wherein X¹ is


41. A compound as claimed in claim 1, wherein X¹ is heteroaryl orheterocyclyl.
 42. A compound as claimed in claim 1, wherein X¹ is


43. A compound as claimed in claim 1, selected from the group consistingof: (3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl (1S)-5-{[(methylamino)carbonyl]amino}-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;1-benzyl-4,4-dimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; benzyl4,4-dimethyl-2-oxo-3-[({([(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;3S)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate;(3R)-4,4-dimethyl-2-oxopyrrolidinyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate;1,4,4-trimethyl-2-oxo-3-pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-benzyl-4,4-dimethylpyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-benzoyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-acetyl-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(phenylacetyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(5-isoxazolylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(4-methyl-1,2,3-thiadiazol-5-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1,3-benzodioxol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1-benzothien-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(2-naphthoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(5-methyl-3-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1H-indol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1H-1,2,3-benzotriazol-5-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(3-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(4-phenylbutanoyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(4-tert-butylphenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-{[2-(4-pyridinyl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(5-methyl-3-phenyl-4-isoxazolyl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(1-methyl-1H-indol-2-yl)carbonyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(3-quinolinylcarbonyl)pyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-([1,1′-biphenyl]-4-ylacetyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(2-phenoxyphenyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1H-indol-2-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-{oxo([(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(3-pyridinylacetyl)pyrrolidinyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(1H-1,2,4-triazol-3-ylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-[(3-methyl-5-isoxazolyl)acetyl]pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1H-indazol-3-ylcarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-{[2-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3-thiazol-4-yl]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-{[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(4-fluorophenyl)acetyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;[1,1′-biphenyl]-4-ylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;tetrahydro-2-furanylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;3-thienylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo([(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;(3S)-tetrahydro-3-furanyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;benzyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;2-phenylethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;(1-phenyl-1H-1,2,3-triazol-4-yl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;2-(2-oxo-1-pyrrolidinyl)ethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;tetrahydro-2H-pyran-2-ylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;tetrahydro-3-furanylmethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;[3-methyl-5-(5-methyl-isoxazol-3-yl)-4-isoxazolyl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;2-(4-methyl-1,3-thiazol-5-yl)ethyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;(5-methyl-3-isoxazolyl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;(2-methyl[1,1′-biphenyl]-3-yl)methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;[5-(2-thienyl)-1,2,4-oxadiazol-3-yl]methyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;(3R)-tetrahydro-3-furanyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;[1,1′-biphenyl]-4-yl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;4-phenoxyphenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;3-phenoxyphenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;2-naphthyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;4-(1,2,3-thiadiazol-4-yl)phenyl(4S)-3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;phenyl3,3-dimethyl-4-[({[(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentyl]amino}carbonyl)oxy]-1-pyrrolidinecarboxylate;(3S)-1-(anilinocarbonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(benzylamino)carbonyl-4.4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1r)-1-phenylethyl]amino}acetyl)pentylcarbamate;)(3S)-4,4-dimethyl-1-{[(2-phenylethyl)amino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(3-pyridinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-{[(3,5-dimethyl-4-isoxazolyl)amino]carbonyl}-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(cyclohexylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(4-cyanoanilino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-{[4-(trifluoromethyl)anilino]carbonyl}pyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate;(3S)-1-[(5-fluoro-2-methylanilino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo([(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(4-morpholinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(1-pyrrolidinylcarbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-[(benzoylamino)carbonyl]-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-({[(4-methylphenyl)sulfonyl]amino}carbonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-4,4-dimethyl-1-(phenylsulfonyl)pyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(benzylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1,3-benzodioxol-5-ylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-4,4-dimethylpyrrolidinyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate;(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate;(3S)-4,4-dimethyl-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]pyrrolidinyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate;and (3S)-4,4-dimethyltetrahydro-3-furanyl1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; or a salt,solvate, or physiologically functional derivative thereof.
 44. Apharmaceutical composition comprising a therapeutically effective amountof a compound as claimed in claim 1, or a salt, solvate, or aphysiologically functional derivative thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.
 45. Amethod of treating a disorder in a mammal, said disorder beingcharacterized by an imbalance between bone resorption and formationwhich can ultimately lead to fracture, comprising: administering to saidmammal a therapeutically effective amount of a compound as claimed inclaim 1 or a salt, solvate or a physiologically functional derivativethereof.
 46. A method of treating a disorder in a mammal, said disorderbeing characterized by bone loss, comprising: administering to saidmammal a therapeutically effective amount of a compound as claimed inclaim 1 or a salt, solvate or a physiologically functional derivativethereof. 47-48. (canceled)
 49. A method of treating osteoporosis,comprising: administering to said mammal a therapeutically effectiveamount of a compound as claimed in claim 1, or a salt, solvate orphysiologically functional derivative thereof.
 50. A method of treatingosteoporosis, comprising: administering to said mammal therapeuticallyeffective amounts of (i) a compound as claimed in claim 1, or a salt,solvate or physiologically functional derivative thereof and (ii) atleast one bone building agent.